Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation

ABSTRACT

The present invention provides imidazothiadiazole compounds of Formula (I); Wherein W, Y, R 0 , R 2 , R 4 , R a , R b , X 1 , X 2 , X 3  and X 4  are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/638,567, filed on Apr. 26, 2012, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention provides novel imidazothiadiazoles and analoguesthereof, which are inhibitors of platelet aggregation and which areuseful in preventing or treating thromboembolic disorders. Thisinvention also relates to pharmaceutical compositions containing thesecompounds and methods of using the same.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), syntheticpentasaccharides, and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increasedrisk of bleeding as well as partial efficacy (relative cardiovascularrisk reduction in the 20 to 30% range). Thus, discovering and developingsafe and efficacious oral or parenteral antithrombotics for theprevention and treatment of a wide range of thromboembolic disordersremains an important goal.

Alpha-thrombin is the most potent known activator of plateletaggregation and degranulation. Activation of platelets is causallyinvolved in atherothrombotic vascular occlusions. Thrombin activatesplatelets by cleaving G-protein coupled receptors termed proteaseactivated receptors (PARs). PARs provide their own cryptic ligandpresent in the N-terminal extracellular domain that is unmasked byproteolytic cleavage, with subsequent intramolecular binding to thereceptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic thesequence of the newly formed N-terminus upon proteolytic activation caninduce signaling independent of receptor cleavage. Platelets are a keyplayer in atherothrombotic events. Human platelets express at least twothrombin receptors, commonly referred to as PAR1 and PAR4 Inhibitors ofPAR1 have been investigated extensively, and several compounds,including vorapaxar and atopaxar have advanced into late stage clinicaltrials. Recently, in the TRACER phase III trial in ACS patients,vorapaxar did not significantly reduce cardiovascular events, butsignificantly increased the risk of major bleeding (Tricoci, P. et al.,N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need todiscover new antiplatelet agents with increased efficacy and reducedbleeding side effects.

There are several early reports of preclinical studies of PAR4inhibitors. Lee, F-Y. et al., “Synthesis of1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as NovelAntiplatelet Agents”, J. Med. Chem., 44(22):3746-3749 (2001) disclosesin the abstract that the compound

“was found to be a selective and potent inhibitor or protease-activatedreceptor type 4 (PAR4)-dependent platelet activation.”

Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “SelectiveInhibition of Protease-activated Receptor 4-dependent PlateletActivation by YD-3”, Thromb. Haemost., 87:1026-1033 (2002). Also, seeChen, H. S. et al., “Synthesis and platelet activity”, J. Bioorg. Med.Chem., 16:1262-1278 (2008).

EP1166785 A1 and EP0667345 disclose various pyrazole derivatives whichare useful as inhibitors of platelet aggregation.

SUMMARY OF THE INVENTION

In has been found that imidazothiadiazole compounds in accordance withthe present invention are PAR4 antagonists which inhibit plateletaggregation in gamma-thrombin induced platelet aggregation assays.Moreover, a compound(s) of the present invention has been shown toinhibit platelet aggregation in an alpha-thrombin induced plateletaggregation assay.

Accordingly, the present invention provides novel imidazothiadiazoles,and analogues thereof, which are PAR4 antagonists and are useful asselective inhibitors of platelet aggregation, including stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof.

The present invention also provides a method for the treatment orprophylaxis of thromboembolic disorders comprising administering to apatient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrug esters thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for themanufacture of a medicament for the treatment or prophylaxis of athromboembolic disorder.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph which shows effectiveness of the Example 13 compoundin inhibiting aggregation of human washed platelets stimulated by 1.5 nMalpha-thrombin over time; and

FIG. 2 is a graph which shows the IC₅₀ of the Example 13 compound ininhibiting alpha-thrombin-induced platelet aggregation.

DETAILED DESCRIPTION

In one embodiment, the present invention provides imidazothiadiazolecompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, of Formula I having the structure:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug ester thereof, wherein:

W is O or S;

R¹ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   C₁-C₄ alkylthio,    -   C₁-C₄ alkylNH—,    -   (C₁-C₄ alkyl)₂N—,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   C₁-C₄ alkylthio,    -   C₁-C₄ alkylNH—,    -   (C₁-C₄ alkyl)₂N—,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂ alkyl,    -   halo-C₁-C₂ alkoxy,    -   CN, and    -   OH;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy, and    -   cyano;

X¹ is selected from the group consisting of CH, N or CR¹⁰;

X², X³ and X⁴ are independently selected from CR³ or N;

R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN,OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, whichcontains 1 to 5 halogens, benzyloxy substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,OCHF₂, di-C₁-C₄-alkylamino, and cyano, and —(CH₂)_(n) ¹-phenylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl; or R⁴ and R⁵can be taken together with the carbon to which they are attached to forma C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member ofwhich is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to10-membered heteroaryl, a 4- to 10-membered heterocyclyl containingcarbon atoms and 1 to 4 additional heteroatoms selected from N, O, andS, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of whichare substituted by 0 to 3 R^(b) groups;

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,C₆-C₁₀ aryl, 5-6-membered heteroaryl, 4- to 10-membered heterocyclyloxyand C₁-C₅ alkyl substituted by 0 to 7 groups independently selected fromhalo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to10-membered heterocyclyloxy and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,    -   C₂-C₄ alkenyl,    -   C₂-C₄ alkynyl,    -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   di-C₁-C₄-alkylaminophenyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl;    -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,    -   amino-C₁-C₄-alkylcarbonyl,    -   4- to 10-membered-heterocyclyl-carbonyl, and        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 8-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl substitutedby 0 to 3 groups independently selected from the group consisting ofhalo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,

R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halois F or Cl;

n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

p, at each occurrence, is selected from 0, 1 and 2.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IAA:

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein Wis O.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

is phenyl or a 6-membered heteroaryl ring, at least one ring member ofwhich is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

is attached at the meta position of

and is selected from the group consisting of C₆-C₁₀ aryl ring, a 5- to10-membered heteroaryl ring, a 4- to 10-membered heterocyclyl ring or aC₃-C₆-membered cycloalkyl ring, wherein each

rings is substituted with 0 to 3 R^(b) groups;

R¹ is selected from the group consisting of:

-   -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl, and C₁-C₄ alkylthio;

R^(1a) is selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, and    -   C₁-C₄ alkylthio;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo,    -   C₁-C₄ alkoxy,    -   CF₃,    -   CF₃O,    -   CHF₂, and    -   OH;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy, and    -   cyano;

X¹ is selected from the group consisting of CH, N or CR¹⁰;

X², X³ and X⁴ are independently selected from CR³ or N;

R³ is selected from the group consisting of H, C₁-C₄ alkoxy, halo, CF₃O,CHF₂O, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens;

R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or R⁴ andR⁵ can be taken together with the carbon to which they are attached toform a C₃-C₆ cycloalkyl ring;

R^(a) is, at each occurrence, independently selected from the groupconsisting of:

-   -   H, halo, OCF₃, NR⁶R⁷, OCHF₂, halo-C₁-C₂-alkyl substituted with 1        to 5 fluorines, CF₃,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₄ alkylthio,    -   OH,    -   CN,    -   NO₂,    -   COOH,    -   C₁-C₄ alkoxycarbonyl,    -   C(═O)NR⁶R⁷,    -   C₁-C₄ alkylsulfonyl, and    -   S(═O)₂NR⁶R⁷;

R^(b) is, at each occurrence, independently selected from the groupconsisting of:

-   -   H, halo, OCF₃, NR⁶R⁷, OCHF₂, halo-C₁-C₂-alkyl substituted with 1        to 5 fluorines, CF₃,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₄ alkylthio,    -   OH,    -   CN,    -   NO₂,    -   COOH,    -   C₁-C₄ alkoxycarbonyl,    -   C(═O)NR⁶R⁷,    -   C₁-C₄ alkylsulfonyl, and    -   S(═O)₂NR⁶R⁷; or

R⁶ and R⁷ are, independently, at each occurrence, selected from thegroup consisting of:

-   -   H,    -   C₁-C₄ alkyl, and    -   —(CH₂)_(n) ¹ phenyl,        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 6-membered heterocyclic ring containing        carbon atoms and 1 to 2 additional heteroatoms selected from N,        NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₄ alkyl and —(CH₂)phenyl;

n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 and 5; and

p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

Y is S or CH═CH—;

X¹ is CH or N;

X², X³ and X⁴ are each independently CR³;

R⁰ is R¹ or R^(1a);

R¹ and R^(1a) are independently selected from the group consisting of:

-   -   C₁-C₄ alkyl,    -   C₁-C₄ alkylthio,    -   C₁-C₄ alkoxy, and    -   halo-C₁-C₂-alkyl which contains 1 to 5 halogens;

R² is H;

R₃ is selected from the group consisting of:

-   -   C₁-C₄ alkoxy,    -   H, and    -   halo; and

R⁴ and R⁵ are each H.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula IA and IB:

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IC, ID, IE and IF:

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IG, IH, IJ and IK:

wherein: W, X, Y and Z are independently selected from C—(R^(a))₀₋₂ orN, at least one of W, X, Y and Z being N.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IL and IM:

wherein:

Het A is selected from the group consisting of pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl; and

is selected from the group consisting of phenyl, naphthyl, pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IP and IQ:

wherein:

Het A is selected from the group consisting of pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl; and

is selected from the group consisting of phenyl, naphthyl pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IA.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IB.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IC.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula ID.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IE.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IF.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IG.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IH.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IJ.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IK.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IL.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IM.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IP.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula IQ.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

R^(a) is selected from the group consisting of H, halo, OCF₃, OCHF₂,NR⁶R⁷, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkylsulfonyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, andC₃-C₆-cycloalkyl; and

R^(b) is selected from the group consisting of H, halo, OCF₃, OCHF₂,NR⁶R⁷, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkylsulfonyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, andC₃-C₆-cycloalkyl,

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinR^(a) and R^(b) are independently selected from the group consisting of:

OH;

CN;

NO₂;

NR⁶R⁷;

carboxy;

halo;

OCF₃;

OCHF₂;

C₁-C₄ alkyl;

halo-C₁-C₂-alkyl substituted with 1 to 5 fluorines;

C₁-C₄ alkoxy;

C₁-C₄ alkoxycarbonyl;

C(═O)NR⁶R⁷;

C₁-C₄ alkylsulfonyl;

S(═O)₂NR⁶R⁷;

aryl substituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,CF₂CH₃, OCHF₂, and cyano;

aryloxy, wherein the aryl is substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

arylthio, wherein the aryl is substituted by 0 to 3 groups independentlyselected from the group consisting of the group consisting of halo,C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

aryl-C₁-C₄-alkoxy, wherein the aryl is substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

C₃-C₆ cycloalkyl substituted by 0 to 3 groups independently selectedfrom the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

C₃-C₆ cycloalkoxy substituted by 0 to 3 groups independently selectedfrom the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

5- to 10-membered heteroaryl-C₁-C₄-alkyl, wherein the heteroaryl issubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₃ alkyl, cyclopropyl, CF₃, OCF₃,OCHF₂, and cyano;

5- to 10-membered heteroaryl-C₁-C₄-alkoxy, wherein the heteroaryl issubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₃ alkyl, cyclopropyl, CF₃, OCF₃,OCHF₂, and cyano;

aryl-C₁-C₄-alkyl, wherein the aryl is substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

4- to 10-membered heterocyclylcarbonyl, wherein the heterocyclyl issubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,OCHF₂, and cyano;

4- to 10-membered heterocyclyl which is substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, OCHF₂, and cyano;

4- to 10-membered heterocyclyl-C₁-C₄-alkyl, wherein the heterocyclyl issubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₃ alkyl, cyclopropyl, CF₃, OCF₃,OCHF₂, and cyano; and

4- to 10-membered heterocyclyl-C₁-C₄-alkoxy, wherein the heterocyclyl issubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₃ alkyl, cyclopropyl, CF₃, OCF₃,OCHF₂, and cyano.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein is

selected from the group consisting of phenyl, naphthyl pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl; and

is selected from the group consisting of phenyl, naphthyl pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O or S;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl, and    -   halo-C₁-C₂ alkoxy;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl, and    -   halo-C₁-C₂ alkoxy;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂ alkyl,    -   halo-C₁-C₂ alkoxy, and    -   OH;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl, and    -   C₁-C₄ alkoxy;

X¹ is selected from the group consisting of CH, N or CR¹⁰;

X², X³ and X⁴ are independently selected from CR³ or N;

R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN,OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, whichcontains 1 to 5 halogens, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3groups independently selected from the group consisting of halo, C₁-C₄alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵can be taken together with the carbon to which they are attached to forma C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member ofwhich is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to10-membered heteroaryl, a 4- to 10-membered heterocyclyl containingcarbon atoms and 1 to 4 additional heteroatoms selected from N, O, andS, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of whichare substituted by 0 to 3 R^(b) groups;

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,    -   C₂-C₄ alkenyl,    -   C₂-C₄ alkynyl,    -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   di-C₁-C₄-alkylaminophenyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl; and        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 6-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), and —(CH₂)_(n)¹phenyl substituted by 0 to 3 groups independently selected from thegroup consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, andcyano,

R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halois F or Cl;

n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O or S;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   C₁-C₄ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₂ alkoxy-C₁-C₂ alkyl,    -   tetrahydrofuran-2-yl;    -   C₁-C₄ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂ alkyl, and    -   halo-C₁-C₂ alkoxy;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₃ alkyl, and    -   C₁-C₂ alkoxy;

X¹ is selected from the group consisting of CH, N or CR¹⁰;

X², X³ and X⁴ are independently selected from CR³ or N;

R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN,OCF₃, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, which contains 1 to 5halogens, benzyloxy substituted by 0 to 3 groups independently selectedfrom the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,di-C₁-C₄-alkylamino, and cyano, and —(CH₂)_(n) ¹-phenyl substituted by 0to 3 groups independently selected from the group consisting of halo,C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵can be taken together with the carbon to which they are attached to forma C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member ofwhich is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to10-membered heteroaryl, a 4- to 10-membered heterocyclyl containingcarbon atoms and 1 to 4 additional heteroatoms selected from N, O, andS, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of whichare substituted by 0 to 3 R^(b) groups;

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,    -   C₂-C₄ alkenyl,    -   C₂-C₄ alkynyl,    -   —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl;    -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,    -   amino-C₁-C₄-alkylcarbonyl,    -   4- to 10-membered-heterocyclyl-carbonyl, and        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 8-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl substitutedby 0 to 3 groups independently selected from the group consisting ofhalo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,

R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halois F or Cl;

n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and

p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O or S;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₄ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₂-C₃ alkenyl,    -   C₂-C₃ alkynyl,    -   C₃-C₄ cycloalkyl,    -   C₁-C₄ alkoxy,    -   C₁-C₄ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl,    -   halo-C₃-C₄ cycloalkyl,    -   halo-C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkylthio;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   halo-C₁-C₂ alkyl, and    -   halo-C₁-C₂ alkoxy;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is selected from the group consisting of:

-   -   H,    -   fluoro,    -   chloro, and    -   CH₃;

X¹ is selected from the group consisting of CH, N or CR¹⁰;

X², X³ and X⁴ are independently selected from CR³ or N;

R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₂-C₃alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylthio, halo, OH, CN,OCF₃, and halo-C₁-C₃-alkyl, which contains 1 to 5 halogens;

R⁴ and R⁵ are independently selected from H, C₁-C₃ alkyl, halo-C₁-C₃alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵can be taken together with the carbon to which they are attached to forma C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member ofwhich is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to10-membered heteroaryl, a 4- to 10-membered heterocyclyl containingcarbon atoms and 1 to 4 additional heteroatoms selected from N, O, andS, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of whichare substituted by 0 to 3 R^(b) groups;

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₁-C₄ alkyleneoxy-C₁-C₄-alkylene,    -   C₂-C₄ alkenyl,    -   —(CR¹⁴R¹⁴)_(n) ¹⁻phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl;    -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,    -   amino-C₁-C₄-alkylcarbonyl,    -   4- to 10-membered-heterocyclyl-carbonyl, and        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 8-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino) and —(CH₂)_(n)¹phenyl substituted by 0 to 3 groups independently selected from thegroup consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, andcyano,

R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, andhalo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl;

n¹, at each occurrence, is selected from 0, 1, 2, 3 or 4; and

p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein:

W is O;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   halo,    -   C₁-C₂ alkyl,    -   cyclopropyl,    -   C₁-C₂ alkoxy,    -   C₁-C₂ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl, and    -   halo-C₃-C₄ cycloalkyl;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   halo,    -   C₁-C₂ alkyl,    -   cyclopropyl,    -   C₁-C₂ alkoxy,    -   C₁-C₂ alkylthio,    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl, and    -   halo-C₃-C₄ cycloalkyl;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   fluoro,    -   chloro,    -   C₁-C₃ alkyl,    -   C₁-C₂ alkoxy, and    -   halo-C₁-C₂ alkyl;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is H;

X¹ is selected from the group consisting of CH or N;

X², X³ and X⁴ are independently selected from CR³;

R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₁-C₃alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which contains 1 to5 halogens;

R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃alkyl, hydroxy-C₁-C₃ alkyl and C₁-C₃ alkoxy-C₁-C₃ alkyl;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl;

B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to10-membered heteroaryl, a 4- to 10-membered heterocyclyl containingcarbon atoms and 1 to 2 additional heteroatoms selected from N, O, andS, and a C₃-C₆ cycloalkyl which may contain unsaturation, all of whichare substituted by 0 to 3 R^(b) groups;

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₂-C₄ alkenyl,    -   —(CR¹⁴R¹⁴)_(n) ¹⁻phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl;    -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, and    -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 8-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino and —(CH₂)_(n) ¹phenyl substituted by 0 to 3groups independently selected from the group consisting of halo, C₁-C₄alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,

n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

p, at each occurrence, is selected from 0, 1 and 2.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O;

R⁰ is R¹ or R^(1a);

Y is S or —CR⁸═CR⁹—;

R¹ is independently selected from the group consisting of:

-   -   C₁-C₂ alkyl,    -   C₁-C₂ alkoxy,    -   C₁-C₂ alkylthio, and    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl;

R^(1a) is independently selected from the group consisting of:

-   -   H,    -   fluoro,    -   chloro,    -   C₁-C₂ alkyl,    -   C₁-C₂ alkoxy,    -   C₁-C₂ alkylthio, and    -   halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is        F or Cl;

R⁸ and R⁹ are independently selected from the group consisting of:

-   -   H,    -   fluoro,    -   chloro,    -   CH₃,    -   OCH₃,    -   CF₃, and    -   CHF₂;        provided that at least one of R^(1a), R⁸ and R⁹ is other than H;

R² is H;

X¹ is selected from the group consisting of CH or N;

X² and X⁴ are CH;

X³ is CR³;

R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₁-C₃alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which contains 1 to5 halogens;

R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl;

is selected from the group consisting of phenyl, naphthyl pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cyclo alkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₂-C₄ alkenyl,    -   —(CR¹⁴R¹⁴)_(n) ¹⁻phenyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl, and    -   phenylcarbonyl;        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 8-membered heterocyclic ring containing        carbon atoms substituted by 0 to 3 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2        additional heteroatoms selected from N, NR¹³, O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H, and C₁-C₃ alkyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₃ alkyl, and halo-C₁-C₂-alkyl;

n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

p, at each occurrence, is selected from 0, 1 and 2.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

W is O;

R⁰ is R¹ or R^(1a);

Y is S or —CH═CH—;

R¹ is independently selected from the group consisting of:

-   -   CH₃,    -   OCH₃,    -   SCH₃,    -   CHFCH₃, and    -   CF₂CH₃;

R^(1a) is independently selected from the group consisting of:

-   -   chloro,    -   CH₃, and    -   OCH₃,

R² is H;

X¹ is CH;

X² and X⁴ are CH;

X³ is CR³;

R³ is selected from the group consisting of OCH₃, fluoro, and chloro; R⁴and R⁵ are independently selected from H and CH₃;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl;

is selected from the group consisting of phenyl, naphthyl pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

R^(a), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independentlyselected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy,C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio;

R^(b), at each occurrence, is independently selected from the groupconsisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴,NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cyclo alkyl, phenyl, and C₁-C₄ alkylthio;

R⁶ and R⁷ are independently, at each occurrence, selected from the groupconsisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, and    -   C₁-C₄-alkoxycarbonyl;        alternatively, R⁶ and R⁷, when attached to the same nitrogen,        combine to form a 4- to 7-membered heterocyclic ring containing        carbon atoms substituted by 0 to 2 groups independently selected        from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂,        OCH₂F, OH, oxo, hydroxy-C₁-C₂-alkyl, C₁-C₃ alkyl and C₁-C₃        alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³,        O and S(O)_(p);

R¹³ is independently, at each occurrence, selected from the groupconsisting of H and C₁-C₃ alkyl;

R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H and C₁-C₃ alkyl

n¹, at each occurrence, is selected from 0, 1, 2 or 3; and

p, at each occurrence, is selected from 0, 1 and 2.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein:

X₁ is CH or N;

R¹ is C₁-C₃ alkoxy or halo-C₁-C₂-alkyl which contains 1 to 5 halogens;

R² is H;

R³ is H, C₁-C₄ alkoxy or halogen;

is selected from the group consisting of phenyl, pyridyl andpyrimidinyl, all of which are substituted with 0 to 2 R^(a) groups;

is selected from the group consisting of:

a) phenyl;

b) phenyl substituted with 1 to 2 R^(b) substituents selected from halo,OH. halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, CN, NO₂,

N(alkyl)₂, CF₃,

C₁-C₄ alkyl, and C₁-C₄ alkoxy;

c) phenyl fused to a heterocyclo group;

d) monocyclic heteroaryl containing 5 or 6 ring members which contain:

-   -   1 oxygen atom,    -   2 nitrogen atoms,    -   2 sulfur atoms,    -   1 nitrogen atom,    -   1 sulfur atom,    -   1 oxygen atom,    -   or combinations thereof, which monocyclic heteroaryl is        substituted with 0 to 2 R^(1p) substituents selected from halo,        CN, NO₂, OH, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy,        halo-C₁-C₄ alkoxy,

N(alkyl)₂, C₁-C₄ alkoxy-C₁-C₄ alkoxy, COOH, C₁-C₄ alkoxycarbonyl,heterocyclyl, or heterocyclylcarbonyl; and

e) bicyclic heteroaryl containing 8 or 9 ring members and which containsa sulfur atom, nitrogen atoms or combinations thereof in the ring.

In yet another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are selected from the examples, preferably a compoundselected from Examples 3 to 114.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are selected from:

Preferably, PAR4 compounds of the invention have IC₅₀s in the FLIPRAssay (described hereinafter) of about 10 μM, preferably 5 μM or less,more preferably 500 nM or less, and even more preferably 10 nM or less.Activity data for a number of these compounds is presented in the tablein Example F.

In some embodiments, the present invention provides at least onecompound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug esters thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition, which includes a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,alone or in combination with another therapeutic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition which further includes another therapeutic agent(s). In apreferred embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are P2Y12 antagonists and/or aspirin. Preferably,the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. Inanother preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent(s)are an anticoagulant or a combination thereof. Preferably, theanticoagulant agent(s) are FXa inhibitors, FXIa inhibitors or thrombininhibitors. Preferably, the FXa inhibitors are apixaban or rivaroxaban.Preferably, the thrombin inhibitor is dabigatran. For examples of FXIainhibitors that may be useful in the present invention see InternationalPatent Application Publication No. WO 2011/10040.

In some embodiments, the present invention provides a method for thetreatment or prophylaxis of a thromboembolic disorder which includes thestep of administering to a subject (for example, a human) in need ofsuch treatment or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugesters thereof.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart orin the peripheral circulation.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, non-ST-elevated myocardialinfarction, atrial fibrillation, myocardial infarction, transientischemic attack, stroke, atherosclerosis, peripheral arterial disease,venous thrombosis, deep vein thrombosis, thrombophlebitis, arterialembolism, coronary arterial thrombosis, cerebral arterial thrombosis,cerebral embolism, kidney embolism, pulmonary embolism, cancer-relatedthrombosis, and thrombosis resulting from medical implants, devices, andprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, and non-ST-elevated myocardialinfarction.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of transient ischemic attack and stroke.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, IAA, IA,IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, acompound selected from one of the examples, more preferably a compoundselected from Examples 3 to 114, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is peripheral arterial disease.

In some embodiments, the present invention includes a method asdescribed above wherein the thromboembolic disorder is selected fromunstable angina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In some embodiments, the present invention includes a method ofinhibiting or preventing platelet aggregation, which includes the stepof administering to a subject (such as a human) in need thereof atherapeutically effective amount of a PAR4 antagonist, which is acompound of Formula I, IAA, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL,IM, IP or IQ, preferably, a compound selected from one of the examples,more preferably a compound selected from Examples 3 to 114, of theinvention.

OTHER EMBODIMENTS OF THE INVENTION

In some embodiments, the present invention provides a process for makinga compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the present invention provides an intermediate formaking a compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the invention provides a method of treatment orprophylaxis of a thromboembolic disorder involving administering to asubject in need thereof (e.g., a human) a therapeutically effectiveamount of a compound that binds to PAR4 (such as a compound of Formula Iof the invention) and inhibits PAR4 cleavage and/or signaling, whereinsaid subject has a dual PAR1/PAR4 platelet receptor repertoire.

In some embodiments, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrug esters thereof, for use intherapy for the treatment or prophylaxis of a thromboembolic disorder.

In some embodiments, the present invention also provides the use of acompound of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrug esters thereof,for the manufacture of a medicament for the treatment or prophylaxis ofa thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Chemistry

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. When nospecific mention is made of the configuration (cis-, trans- or R or S)of a compound (or of an asymmetric carbon), then any one of the isomersor a mixture of more than one isomer is intended. The processes forpreparation can use racemates, enantiomers, or diastereomers as startingmaterials. All processes used to prepare compounds of the presentinvention and intermediates made therein are considered to be part ofthe present invention. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatography or fractional crystallization. Compounds of the presentinvention, and salts thereof, may exist in multiple tautomeric forms, inwhich hydrogen atoms are transposed to other parts of the molecules andthe chemical bonds between the atoms of the molecules are consequentlyrearranged. It should be understood that all tautomeric forms, insofaras they may exist, are included within the invention.

The molecular weight of compounds of the present invention is preferablyless than about 800 grams per mole.

As used herein, the term “alkyl” or “alkylene”, alone or as part ofanother group, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 10 carbons orthe specified number of carbon atoms. For example, “C₁₋₁₀ alkyl” (oralkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl” denotesalkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted orsubstituted with at least one hydrogen being replaced by anotherchemical group. Example alkyl groups include, but are not limited to,methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl(e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl), as well as chain isomers thereof, and the like aswell as such groups which may optionally include 1 to 4 substituentssuch as halo, for example F, Br, Cl, or I, or CF₃, alkyl, alkoxy, aryl,aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy,hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl,alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol,haloalkyl, trihaloalkyl, and/or alkylthio as well as (═O), OR_(a),SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c),—SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂,—C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b), —C(═O)(C₁-C₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁-C₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), —NR_(a)(C₁-C₄alkylene)CO₂R_(b), ═N—OH, ═N—O-alkyl, wherein R_(a) and R_(b) are thesame or different and are independently selected from hydrogen, alkyl,alkenyl, CO₂H, CO₂(alkyl), C₃-C₇cycloalkyl, phenyl, benzyl, phenylethyl,naphthyl, a 4- to 7-membered heterocyclo, or a 5- to 6-memberedheteroaryl, or when attached to the same nitrogen atom may join to forma heterocyclo or heteroaryl, and R_(c) is selected from same groups asR_(a) and R_(b) but is not hydrogen. Each group R_(a) and R_(b) whenother than hydrogen, and each R_(c) group optionally has up to threefurther substituents attached at any available carbon or nitrogen atomof R_(a), R_(b), and/or R_(c), said substituent(s) being the same ordifferent and are independently selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₆)alkenyl, hydroxy, halogen, cyano, nitro, CF₃,O(C₁-C₆ alkyl), OCF₃, C(═O)H, C(═O)(C₁-C₆ alkyl), CO₂H, CO₂(C₁-C₆alkyl), NHCO₂(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, N(CH₃)₃ ⁺, SO₂(C₁-C₆ alkyl), C(═O)(C₁-C₄ alkylene)NH₂,C(═O)(C₁-C₄ alkylene)NH(alkyl), C(═O)(C₁-C₄ alkylene)N(C₁-C₄ alkyl)₂,C₃-C₇ cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy,naphthyl, a 4- to 7-membered heterocyclo, or a 5- to 6-memberedheteroaryl. When a substituted alkyl is substituted with an aryl,heterocyclo, cycloalkyl, or heteroaryl group, said ringed systems are asdefined below and thus may have zero, one, two, or three substituents,also as defined below.

“Alkenyl” or “alkenylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon double bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups. Examples of alkenyl include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, and 4-methyl-3-pentenyl, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, and/or alkylthio.

“Alkynyl” or “alkynylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon triple bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio.

The term “alkoxy” or “alkyloxy”, alone or as part of another group,refers to an —O-alkyl group, where alkyl is as defined above. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy”, alone or as part of anothergroup, represents an alkyl group or alkoxy group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example methyl-S— and ethyl-S—.

“Halo” or “halogen”, alone or as part of another group, includes fluoro,chloro, bromo, and iodo.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 to 7 halogens, preferably 1 to 4halogens, preferably F and/or Cl. Examples of haloalkyl include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl, 1,1-difluoroethyl,1-fluoroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 to 7 fluorine atoms, preferably 1 to 4fluorine atoms.

“Halo-C₁-C₂-alkoxy” or “haloalkyloxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl), and tricyclic alkyl, containing a total of 3 to 10carbons forming the ring (C₃-C₁₀ cycloalkyl), and which may be fused to1 or 2 aromatic rings as described for aryl, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl, norbornyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl, as well as such groups including 2free bonds and thus are linking groups.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆₋₁₀ aryl” or “aromatic residue”may be unsubstituted or substituted with 1 to 3 groups selected from OH,OC₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃,OCHF₂, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₃ alkyl, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclo” or “heterocyclic”group is intended to mean a stable 4- to 14-membered monocyclic,bicyclic or tricyclic heterocyclic ring which is saturated or partiallyunsaturated and which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, NH, Oand S and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may optionally be substituted on carbon or on anitrogen atom if the resulting compound is stable, with 1 to 3 groupsselected from OH, OC₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H,N(CH₃)₂, CF₃, OCF₃, OCHF₂, ═O, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₃ alkyl, CO₂H and CO₂CH₃. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. Spiro and bridgedrings are also included in the definition of heterocycle. A bridged ringoccurs when one or more atoms (i.e., C, O, N, or S) link twonon-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge. When the term “heterocycle” is used, itis not intended to include heteroaryl.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclo groups include quinuclidinyl.

Preferred heterocyclo groups include

which optionally may be substituted.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are unsubstitutedor substituted with 1 to 3 groups selected from OH, OC₁-C₃ alkoxy, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, OCHF₂, ═O,C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₃ alkyl, CO₂H and CO₂CH₃. Thenitrogen atom is substituted or unsubstituted (i.e., N or NR wherein Ris H or another substituent, if defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). Bridged rings are also included in the definition ofheteroaryl. A bridged ring occurs when one or more atoms (i.e., C, O, N,or S) link two non-adjacent carbon or nitrogen atoms. Examples ofbridged rings include, but are not limited to, one carbon atom, twocarbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

Preferred heteroaryl groups include

and the like.

When the term “unsaturated” is used herein to refer to a ring or group,which group may be fully unsaturated or partially unsaturated.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals. The group R_(e) can be selectedfrom alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substitutedalkenyl, or substituted alkynyl, as defined herein, or when appropriate,the corresponding bivalent group, e.g., alkylene, alkenylene, and thelike.

The designation “

” or

attached to a ring or other group refers to a free bond or linkinggroup.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases in which there are quaternary carbonatoms in compounds of the present invention, these can be replaced bysilicon atoms, provided they do not form Si—N or Si—O bonds.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0 to 3 R^(3a), then said group mayoptionally be substituted with up to three R^(3a) groups, and at eachoccurrence R^(3a) is selected independently from the definition ofR^(3a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V. Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and-   f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods and    Principles in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2^(nd) edition,reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and ProdrugMetabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH,Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinal Chemistry, 3rd Edition, Academic Press, San Diego, Calif.(2008).

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., ¹²C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogenincluding tritium and deuterium), are also provided herein. Suchcompounds have a variety of potential uses, e.g., as standards andreagents in determining the ability of a potential pharmaceuticalcompound to bind to target proteins or receptors, or for imagingcompounds of this invention bound to biological receptors in vivo or invitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layerchromatography, “SM” for starting material, “NMR” for nuclear magneticresonance spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “tlc” for thin layer chromatography.“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl AcOH acetic acid MeOH methanol EtOHethanol EtOAc ethyl acetate Et₂O diethyl ether i-PrOH or IPA isopropanolHOAc acetic acid BOP reagent benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorophosphate BBr₃ boron tribromide Boctert-butyloxycarbonyl cDNA complimentary DNA CDCl₃ deuterated chloroformCH₂Cl₂ dichloromethane CH₃CN acetonitrile ACN acetonitrile DABCO1,4-diazabicyclo[2.2.2]octane DCE 1,2 dichloroethane DCM dichloromethaneDCC dicyclohexylcarbodiimide DIAD diisopropyl azodicarboxylate DIEA orDIPEA N,N-diisopropylethylamine DME 1,2-dimethoxyethane DMF dimethylformamide DMAP N,N-dimethylaminopyridine DMSO dimethyl sulfoxide DPPAdiphenyl phosphoryl azide EDC (or EDC•HCl) or3-ethyl-3′-(dimethylamino)propyl- EDCI (or EDCI•HCl) or carbodiimidehydrochloride EDAC or 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride EDTA ethylenediaminetetraacetic acid HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HCl hydrochloric acid HEPES4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid Hex hexane HOBt orHOBT 1-hydroxybenzotriazole monohydrate Hunig's baseN,N-diisopropylethyl amine LAH lithium aluminum hydride LDA Lithiumdiisopropylamide LiHMDS Lithium bis(trimethylsilyl) amide mCPBA orm-CPBA meto-chloroperbenzoic acid NMM N-methylmorpholine Pd/C palladiumon carbon PPA polyphosphoric acid PS polystyrene PXPd2 bis[di-tert-butylphosphinous chloride-kP]di-m- chlorodichloro dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidino- phosphonium hexafluorophosphateTEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TRIStris(hydroxymethyl)aminomethane KOAc potassium acetate K₃PO₄ potassiumphosphate MgSO₄ magnesium sulfate NaCl sodium chloride NaH sodiumhydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₃ sodiumsulfite Na₂SO₄ sodium sulfate NH₃ ammonia NH₄Cl ammonium chloride NH₄OHammonium hydroxide OTs tosylate, para-toluenesulfonate PBr₃ phosphoroustribromide Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0)(S,S)-EtDuPhosRh(I) (+)-1,2-bis((2S,5S)-2,5-diethyl- phospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Wuts et al. (Greene's Protective Groups In OrganicSynthesis, 4th Edition, Wiley-Interscience (2006)).

Compounds of formula I of this invention can be obtained by condensationof an amine of formula III with a ketone of formula IV which contains aleaving group Z such as a bromide, iodide or tosylate and a protectinggroup PG such as benzyl as shown in Scheme 1. Both compounds of formulaIII and IV are commercially available or can be prepared by means knownto one skilled in the art. This condensation is promoted by heating,either thermally or preferably by microwave irradiation. The protectinggroup can be removed by methods known in the art, such as BCl₃ at −78°C. in the presence of pentamethylbenzene. Subsequent alkylation usingeither an alcohol VI under Mitsunobu conditions or a bromide VII in thepresence of base such as potassium carbonate provides the compounds ofFormula I. Alcohols and bromides VI and VII are commercially availableor can be prepared by methods known in the art.

Alternatively, compounds of Formula I can be prepared from compounds offormula IX upon activation of the thiomethyl group by oxidation to asulfone X as shown in Scheme 2. This allows introduction of a variety ofnucleophiles as groups R⁰ such as alcohols, thiols and amines in thepresence of a base such as potassium carbonate or sodium hydride eitherneat or in a polar, aprotic solvent such as dimethylformamide to givecompounds XI. Compounds XI can be converted to compounds of Formula I(where X³ is CR³) by removal of the protecting group (PG) and alkylationas discussed in Scheme 1.

Substituted benzofurans bearing α-bromoketone substituents at the2-position (XV) can be prepared as shown in Scheme 3. o-Hydroxybenzaldehydes XII can be prepared by methods known to one skilled in theart of organic synthesis, and can be condensed with ketones of formulaXIII bearing a leaving group Q such as chloro, bromo or tosyloxy, togive benzofurans XIV. Bromination of compounds of formula XIV affordsbromoketones XV, which can be condensed with a substitutedaminoheterocycle III according to Scheme 1 to give compounds of FormulaI. Bromoketones XV are a specific subset of compounds IV in Scheme 1.

Benzoxazole compounds of Formula I can be prepared starting fromsubstituted aminoheterocycle III and pyruvate esters of formula XVIwhich contain a leaving group Z such as a bromide, iodide or tosylate asshown in Scheme 4. Both compounds of formula III and XVI arecommercially available or are available by means known to one skilled inthe art. Following condensation and saponification of the ester XVII toform acid XVIII, amino phenols of formula XIX are coupled to form amidesof the formula XX, which can be cyclized under acid catalysis to formbenzoxazole compounds of formula XXI. These can be deprotected andalkylated as shown in Scheme 1 to provide compounds of Formula I (whereX³ is CR³).

Aminoheterocycles XXIV can be prepared from carbon disulfide (XXII) viathe thioxanthate intermediate XXIII. These aminoheterocycles are usefulfor the preparation of compounds of Formula I.

Aminoheterocycles XXX, which are useful intermediates for preparation ofcompounds of Formula I where Y=—CH₂CH₂—, can be prepared from ketoestersXXV. Cyclization with hydrazine, followed by oxidation of XXVI withbromine gives pyridazinones XXVII. Chlorination to form XXVII,displacement with hydrazine to form XXIX, and subsequent hydrogenationprovides aminoheterocycles XXX, which are a specific subset of compoundsIII in Scheme 1. As such, these aminoheterocycles are useful for thepreparation of compounds of Formula I.

EXAMPLES

The following compounds of the invention have been prepared, isolatedand characterized using the methods disclosed herein. They demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention. In the experimental procedures, solution ratiosexpress a volume relationship, unless stated otherwise. NMR chemicalshifts (δ) are reported in parts per million (ppm). Products wereanalyzed by reverse phase analytical HPLC using the following methods:

Method A: Column: Waters Xbridge 19×100 mm, 5 um C18, Mobile Phase:A=5:95 Acetonitrile:Water, B=95:5 Acetonitrile:Water, Modifier=0.05%TFA, Wavelength: 220 nm.

Method B: Column ZORBAX® XDB-C18 3.5 microns, 4.6×30 mm; Mobile Phase:A=MeOH:H₂O:TFA (95:5:05), B=MeOH:H₂O:TFA (5:95:05).

Method C: SunfireC18 3.5 microns column (4.6×30 mm) eluted at 3 mL/minwith a 2 min. gradient from 100% A to 100% B (A: 5% methanol, 94.95%water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220 nm).

Method D: Eclipse XDB-C18 3.5 microns column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% methanol,94.95% water, 0.05% TFA; B: 5% water, 94.95% methanol, 0.05% TFA, UV 220nm).

Method E: Eclipse XDB-C18 3.5 microns column (4.6×30 mm) eluted at 3mL/min with a 2 min gradient from 100% A to 100% B (A: 5% acetonitrile,94.95% water, 0.05% TFA; B: 5% water, 94.95% acetonitrile, 0.05% TFA, UV220 nm).

Example 12-Methoxy-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

1A. 5-(Benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one

A solution of5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (30.00 g,0.134 mol) in N,N-dimethylformamide (400 mL) was treated with powderedanhydrous potassium carbonate (19.41 g, 0.14 mol) added all at once. Theresulting mixture was stirred in vacuo for 10 min. and then flushed withnitrogen. The reaction flask was placed in a water bath (22° C.) antreated with benzyl bromide (24.03 g, 0.14 mol) added dropwise over 15min. The resulting mixture was then stirred at 22° C. for 18 h (nostarting material left by tlc). The solid was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (500 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. Crystallization form ethyl acetate (50 mL) and hexane(150 mL) gave 35.17 g of5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one aslarge colorless prisms. Chromatography of the mother liquors on silicagel (4×13 cm, elution toluene-ethyl acetate 0-5%) gave 6.64 g ofadditional material to afford a total yield of 41.81 g (99%). HRMS(ESI)calcd for C₁₈H₁₉O₅ [M+H]⁺ m/z 315.1227. found 315.1386. ¹H NMR (CDCl₃,600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04(d, J=2.03 Hz, 1H), 6.15 (d, J=2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36(broad t, 2H), 7.52 (broad d, 2H).

1B. 2-(Benzyloxy)-6-hydroxy-4-methoxybenzaldehyde

A solution of5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one(Example 1A, 6.76 g, 21.5 mmol) in dichloromethane (120 mL) was cooledto −78° C. and treated with 43 mL (64.5 mmol) of a 1.5 M solution ofdiisobutylaluminum hydride in toluene added dropwise over 20 min. Theresulting mixture was then stirred at −78° C. for 3 h. The reactionmixture was quenched by the careful addition of methanol (5 mL) addeddropwise over 15 min, followed by 1N hydrochloric acid (50 mL) addeddropwise over 15 min. The cooling bath was then removed and anadditional 150 mL of 1N hydrochloric acid was added over 20 min. Themixture was then stirred at 22° C. for 2 h and diluted withdichloromethane (400 mL). The organic phase was collected and theaqueous phase (pH˜1) was extracted with dichloromethane (3×50 mL). Thecombined organic extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residual oil wasdiluted with tetrahydrofuran (70 mL), treated with 10 mL of 0.1Nhydrochloric acid and stirred at 20° C. for 2 h. The reaction mixturewas diluted with ethyl acetate (300 mL), washed with brine, dried overanhydrous magnesium sulfate, evaporated in vacuo to give a clear oil.Chromatography on silica gel (4×13 cm, elution toluene) gave 4.08 g (73%yield) of the title aldehyde as a clear oil which solidified onstanding. LC (Method C): 2.237 min. HRMS(ESI) calcd for C₁₅H₁₅O₄ [M+H]⁺m/z 259.0965. found 259.1153. ¹H NMR (CDCl₃, 600 MHz) δ 3.80 (s, 3H),5.07 (s, 2H), 5.97 (d, J=2.1 Hz, 1H), 6.01 (d, J=2.1 Hz, 1H), 7.3-7.4(m, 5H), 10.15 (s, 1H), 12.49 (s, 1H).

1C. 1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)ethanone

A solution of 2-(benzyloxy)-6-hydroxy-4-methoxybenzaldehyde (Example 1B,3.46 g, 13.4 mmol) in N,N-dimethylformamide (50 mL) was treated withpowdered anhydrous cesium carbonate (4.58 g, 14.05 mmol) added all atonce. The resulting mixture was stirred in vacuo for 10 min. and thenflushed with nitrogen. The reaction flask was placed in a water bath(22° C.) an treated with chloroacetone (1.74 g, 18.7 mmol) addeddropwise over 5 min. The resulting mixture was then stirred at 22° C.for 18 h (no starting aldehyde left by tlc and formation of theintermediate alkylated aldehyde). The solid was filtered and washed withN,N-dimethylformamide. The filtrate was evaporated in vacuo and theresidual oil was diluted with ethyl acetate (300 mL), washed with cold0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. Afterdrying over anhydrous magnesium sulfate, evaporation of the solvent gavea thick syrup. This syrup was diluted with tetrahydrofuran (50 mL) andethyl acetate (50 mL), treated p-toluenesulfonic acid monohydrate (0.2g) and stirred at 20° C. for 1 h (tlc indicated complete cyclization ofthe intermediate alkylated aldehyde to the benzofuran). The reactionmixture was diluted with ethyl acetate (300 mL), washed with saturatedsodium bicarbonate and brine. After drying over anhydrous magnesiumsulfate, evaporation of the solvent gave a thick syrup. Chromatographyon silica gel (4×12 cm, elution toluene-ethyl acetate 2-4%) gave 3.51 g(88% yield) of the title benzofuran as a yellow solid. Recrystallizationfrom ethyl acetate (10 mL) and hexane (20 mL) gave the title material aslarge yellow prisms (3.15 g). LC (Method A): 2.148 min. HRMS(ESI) calcdfor C₁₈H₁₇O₄ [M+H]⁺ m/z 297.1121. found 297.1092. ¹H NMR (CDCl₃, 600MHz) δ 2.51 (s, 3H), 3.82 (s, 3H), 5.13 (s, 2H), 6.37 (d, J=1.77 Hz,1H), 6.63 (broad s, 1H), 7.34 (broad t, 1H), 7.39 (broad t, 2H), 7.44(broad d, 2H), 7.55 (d, J=0.7 Hz, 1H).

1D. 1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone

A 250-mL, three-necked flask is equipped with a magnetic stirring barand purged with a nitrogen atmosphere was charged with anhydroustetrahydrofuran (25 mL) followed by 9.3 mL (9.3 mmol) of a 1M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture wascooled to −78° C. and treated with a solution of1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone (Example 1C, 2.40 g,8.1 mmole) in tetrahydrofuran (20 mL) added dropwise over 10 min. Theresulting mixture was then stirred at −78° C. for 45 min. Thenchlorotrimethylsilane (1.18 mL, 9.31 mmol) was added dropwise over 5 minand the resulting solution was stirred at −78° C. for another 20 min.The cooling bath was then removed and the mixture is allowed to warm toroom temperature over 30 min. The reaction mixture was then quenched byaddition to a cold solution of ethyl acetate (200 mL), saturated sodiumbicarbonate (30 mL) and ice. The organic phase was rapidly dried overanhydrous magnesium sulfate (magnetic stirring) and evaporated in vacuoto give the silyl enol ether as an oil which is co-evaporated withtoluene (20 mL). The silyl enol ether was then dissolved in drytetrahydrofuran (40 mL), cooled to −20° C. and treated with solid sodiumbicarbonate (0.10 g) followed by N-bromosuccinimide (1.44 g, 8.1 mmol)added in small portions over 15 min. The reaction mixture was allowed towarm to 0° C. over 2 h and then quenched by addition of ethyl acetate(300 mL) and saturated sodium bicarbonate. The organic phase was washedwith brine, dried over anhydrous magnesium sulfate and evaporated togive an orange oil. Chromatography on silica gel (4×12 cm, elutiontoluene-ethyl acetate 0-5%) gave 2.62 g (86% yield) of the titlebromomethylketone as a yellow solid. Recrystallization from ethylacetate (10 mL) and hexane (20 mL) gave yellow prisms (2.30 g). LC(Method B): 1.977 min. HRMS(ESI) calcd for C₁₈H₁₆BrO₄ [M+H]⁺ m/z375.0226. found 375.0277. ¹H NMR (CDCl₃, 600 MHz) δ 3.84 (s, 3H), 4.33(s, 2H), 5.14 (s, 2H), 6.38 (d, J=1.76 Hz, 1H), 6.64 (broad s, 1H), 7.35(broad t, 1H), 7.40 (broad t, 2H), 7.44 (broad d, 2H), 7.70 (s, 1H).

1E.6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A mixture of 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone(Example 1D, 3.00 g, 8.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine(1.65 g, 9.16 mmol) in isopropanol (100 mL) was heated is a pressureflask equipped with a magnetic stirring bar at 78-80° C. for 18 h(homogeneous after 20 min and then formation of a precipitate after 2h). The cooled mixture is then transferred into five 20 mL microwavevials and then heated in a microwave apparatus to 150° C. for 30 min.Each vial was then diluted with dichloromethane (250 mL) washed withsaturated sodium bicarbonate (25 mL) and brine (25 mL), dried overanhydrous magnesium sulfate. The fractions were combined andconcentrated in vacuo. Chromatography of the orange-brown residual solidon silica gel (4×10 cm, slow elution with dichloromethane due to poorsolubility) gave 2.96 g of the title imidazothiadiazole contaminatedwith some 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)ethanone. The solidmaterial was triturated with ethyl acetate (20 mL), filtered, washedwith ethyl acetate (10 ml) and dried in vacuo to give 2.34 g (64% yield)of pure title imidazothiadiazole as an off white solid which is used assuch for the next step. LC (Method B): 2.188 min. HRMS(ESI) calcd forC₂₀H₁₅BrN₃O₃S [M+H]⁺ m/z 456.00175. found 456.00397. ¹H NMR (CDCl₃, 600MHz) δ 3.82 (s, 3H), 5.16 (s, 2H), 6.38 (d, J=1.67 Hz, 1H), 6.66 (broads, 1H), 7.15 (s, 1H), 7.31 (broad t, 1H), 7.38 (broad t, 2H), 7.45(broad d, 2H), 8.02 (s, 1H).

1F.6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A solution of6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(Example 1E, 2.30 g, 5.04 mmol) in a mixture of dichloromethane (180 mL)and methanol (45 mL) was treated at 22° C. with 4.2 mL of a 25 wt. %solution of sodium methoxide in methanol (0.2 mmol) added in oneportion. More methanol (45 mL) was added and the mixture was stirred for1 h. The reaction mixture was quenched by the addition of 25 mL of 1Nhydrochloric acid followed by 20 ml of saturated sodium bicarbonate. Thesolvent was evaporated under reduced pressure and the residue wasdiluted with dichloromethane (400 mL), washed with brine, dried overanhydrous magnesium sulfate and evaporated in vacuo. Chromatography ofthe residue on silica gel (3×10 cm, elution with dichloromethane-ethylacetate 0-4%) gave 1.70 g (83% yield) of the title compound as a whitesolid. This material was recrystallized from ethyl acetate (30 mL pergram, 80% recovery) to give white needles. LC (Method A): 2.293 min.HRMS(ESI) calcd for C₂₁H₁₈N₃O₄S [M+H]⁺ m/z 408.1013. found 408.1024. ¹HNMR (CDCl₃, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37(d, J=1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t,1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).

1G.6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A mixture of6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(Example 1F, 1.250 g, 3.06 mmol) and pentamethylbenzene (3.17 g, 21.4mmol) in dichloromethane (200 mL) was cooled to −78° C. under a nitrogenatmosphere and then treated immediately (to avoid crystallization) with8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethaneadded dropwise over 3 min. The resulting mixture was stirred at −78° C.for 1 h. The reaction mixture was then quenched by the addition of asolution of sodium bicarbonate (6 g) in water (100 mL) added in oneportion. The cooling bath was removed and the resulting mixture wasstirred at room temperature for 1 h. The solid formed was filtered,washed successively with water (50 m) and dichloromethane (50 mL). Thefilter cake was allowed to soak with anhydrous ethanol (15 ml) and thensucked dry. The white solid obtained was then dried under vacuum for 24h to give 0.788 g (80% yield) of pure title material (>95% by hplc). Thecombined filtrate and washings were diluted with dichloromethane (600mL) and stirred in a warm water bath till the organic phase was clearwith no apparent solid in suspension. The organic phase was collected,dried over anhydrous magnesium sulfate and rapidly filtered while stillwarm. The filtrate was evaporated and the residue (product andhexamethylbenzene) was triturated with toluene (20 mL), the solidcollected and washed with toluene (20 mL) to give 0.186 g (19% yield,99% combined yield) of title material as a tan solid (>95% by hplc). LC(Method B): 1.444 min. HRMS(ESI) calcd for C₁₄H₁₂N₃O₄S [M+H]⁺ m/z318.0543. found 318.0578. ¹H NMR (DMSO-d₆, 600 MHz) δ 3.71 (s, 3H), 4.16(s, 3H), 6.21 (d, J=1.87 Hz, 1H), 6.61 (broad s, 1H), 6.95 (s, 1H), 8.29(s, 1H), 9.96 (s, 1H).

Example 12-Methoxy-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

Into a 16×100 mm Wheaton tube was added(3-(pyrimidin-5-yl)phenyl)methanol (28 mg, 0.150 mmol) followed with6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 16 mg, 0.050 mmol) and triphenylphosphine (26 mg, 0.100mmol). The vial was capped with septum cap. Air was then evacuated andthe vial was purged with N₂. To the reaction mixture was then added DIAD(39 μL, 0.200 mmol) via syringe followed with THF (0.5 mL, 0.1M). Thereaction was stirred at room temperature overnight, then placed inSPEEDVAC® to dry for 2 h at 40° C. The crude material was dissolved inDMF (1.5 mL) and purified on Prep HPLC (HPLC Waters System, Column:Waters Xbridge 19×100 mm, 5 um C18, Mobile Phase:A=5:95Acetonitrile:Water, B=95:5 Acetonitrile:Water, Modifier=0.05% TFA,Wavelength: 220 nm) to give the title material (0.63 mg, 2%). LC (MethodA): 2.75 min. MS(ESI) calcd for C₂₅H₁₉N₅O₄S [M+H]⁺ m/z 485.1158. found486.04.

Example 22-Methoxy-6-(6-methoxy-4-((3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

2A. (3′-(Trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol

In a 4 mL vial, palladium(II) acetate (1.3 mg, 5.79 μmol),triphenylphosphine (4 mg, 0.015 mmol), 2M aqueous solution of sodiumcarbonate (0.56 mL, 1.120 mmol) and water (0.37 mL, 20.54 mmol) weresuccessively added to a mixture of (3-(trifluoromethyl)phenyl)boronicacid (161 mg, 0.848 mmol) and (3-iodophenyl)methanol (0.1 mL, 0.787mmol) in 1-propanol (1.5 mL, 19.97 mmol) under nitrogen. The mixture wasstirred at 95° C. for 4 h. The mixture was quenched with water and theproduct was extracted three times with AcOEt. The combined organiclayers were washed twice with 1:1 sat. NaHCO₃:water, once with brine,dried over anh. MgSO₄ and concentrated. The residue was purified on ISCOusing a REDISEP® Gold 12 g column (Hex/EtOAc) to give the title material(192 mg, 97%) as a clear oil. LC (Method B): 2.099 min. MS(ESI) calcdfor C₁₄H₁₀F₃ [M+H]⁺-H₂O m/z 235.0813. found 235.0753. ¹H NMR (400 MHz,acetone-d₆) ppm 7.91-8.01 (m, 2H) 7.67-7.78 (m, 3H) 7.61 (dt, J=7.4, 1.8Hz, 1H) 7.45-7.50 (m, 1H) 7.41-7.45 (m, 1H) 4.74 (d, J=5.9 Hz, 2H) 4.30(t, J=5.9 Hz, 1H).

Example 22-Methoxy-6-(6-methoxy-4-((3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, benzene was added to6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 28 mg, 0.088 mmol) and the mixture was sonificated 30 sec.and concentrated in vacuo. The procedure was repeated once to removetraces of water in the starting material. Triphenylphosphine (58 mg,0.221 mmol) was added and the mixture was dried on high vacuum for 10min. To this mixture (3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol(Example 3A, 70 mg, 0.278 mmol) and THF (1.5 mL) were added and themixture was sonificated for 5 min. A solution of diisopropylazodicarboxylate (0.045 ml, 0.231 mmol) in THF (1 mL) was then addeddropwise on 5 min. and the yellow solution was sonificated for 30 min.and stirred 18 h at room temperature. The reaction mixture was dilutedin CH₂Cl₂ and washed once with sat. NaHCO₃, once with brine, dried onanhydrous Na₂SO₄ and concentrated. The residue was purified on ISCOusing a REDISEP® Gold 12 g column (CH₂Cl₂/EtOAc) to give the titlematerial (28 mg, 58%) as a light beige solid after lyophilization inACN/water. LC (Method B): 2.59 min. MS(ESI) calcd for C₂₈H₂₁F₃N₃O₄S[M+H]⁺ m/z 552.1199, 553.123. found 552.1221, 552.1241. ¹H NMR (400 MHz,DMSO-d₆) ppm 8.38 (s, 1H) 8.01-8.04 (m, 1H) 8.00 (s, 1H) 7.90 (s, 1H)7.70-7.78 (m, 3H) 7.53-7.61 (m, 2H) 7.00 (d, J=0.8 Hz, 1H) 6.84 (dd,J=2.0, 0.8 Hz, 1H) 6.57 (d, J=1.6 Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.80(s, 3H).

Preparation of Benzylic Alcohols

The following benzylic alcohols were prepared according to the proceduredescribed in Example 2A using (3-iodophenyl)methanol and thecorresponding boronic acids and were employed in preparing compounds ofthe Examples as indicated.

Structure HPLC (Employed in LCMS Retention preparation of Calc. Calc.LCMS [M + Time Example compound [M + H]⁺ [M + H]⁺ − [M + H]⁺ H]⁺ −(Min)/ as indicated) Formula m/z H₂O m/z m/z H₂O m/z Method NMR

C₁₅H₁₂OS 241.0682 223.0576 241.07  223.0596 2.153/B ¹H NMR (400 MHz,acetone) ppm 7.90-7.96 (m, 1 H) 7.83- 7.88 (m, 1 H) 7.81 (dt, J = 2.4,0.9 Hz, 1 H) 7.78 (d, J = 0.8 Hz, 1 H) 7.65-7.71 (m, 1H) 7.44 (t, J =7.5 Hz, 1 H) 7.32- 7.41 (m, 3 H) 4.72 (d, J = 5.9 Hz, 2 H) 4.34 (t, J =5.7 Hz, 1 H)

C₁₂H₁₃NO₂ 204.1019 204.1052 1.621/B ¹H NMR (400 MHz, acetone) ppm7.40-7.48 (m, 1 H) 7.33- 7.40 (m, 2 H) 7.24 (dt, J = 7.2, 1.7 Hz, 1 H)4.62-4.73 (m, 2 H) 4.25-4.32 (m, 1 H) 2.40 (s, 3 H) 2.22 (s, 3 H)

C₁₁H₁₀O₂ 175.0754 157.0648 175.0779 157.0678 1.701/B ¹H NMR (400 MHz,acetone) ppm 7.96-8.05 (m, 1H) 7.62- 7.65 (m, 1H) 7.57-7.61 (m, 1 H)7.47 (dt, J = 7.4, J = 7.4, 1. Hz, 1 H) 7.34 (t, J = 7.6 Hz, 1H)

C₁₆H₁₈N₂O₂ 271.14  271.2   1.163/B ¹H NMR (400 MHz, acetone) δ ppm 8.46(dd, J = 2.7, 0.8 Hz, 1H) 7.85 (dd, J = 8.8, 2.5 Hz, 1H) 7.58-7.62 (m,1H) 7.45-7.50 (m, 1H) 7.39 (t, J = 7.6 Hz, 1H) 7.28-7.34 (m, 1H) 6.88(dd, J = 8.6, 0.8 Hz, 1H) 4.69 (d, J = 6.3 Hz, 2H) 4.21 (t, J = 5.9 Hz,1H) 3.73- 3.79 (m, 4H) 3.51-3.58 (m, 4H)

Example 32-Methoxy-6-(6-methoxy-4-((3-(pyrimidin-2-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

3A. (3-(Pyrimidin-2-yl)phenyl)methanol

In a 4 mL vial, palladium(II) acetate (0.9 mg, 4.01 μmol),triphenylphosphine (2.7 mg, 10.29 μmol), 2M aqueous solution of sodiumcarbonate (0.55 ml, 1.100 mmol) and water (0.3 ml, 16.65 mmol) weresuccessively added to a mixture of 2-bromopyrimidine (120 mg, 0.755mmol) and (3-(hydroxymethyl)phenyl)boronic acid (121 mg, 0.796 mmol) in1-propanol (1.5 ml, 19.97 mmol) under nitrogen. The mixture was stirredat 95° C. for 2.5 hours. The mixture was quenched with water and theproduct was extracted three times with AcOEt. The combined organiclayers were washed once with sat. NaHCO₃, once with brine, dried overanh. Na₂SO₄ and concentrated. The residue was purified on ISCO using aREDISEP® Gold 12 g column (Hex/EtOAc) to give the title material (52 mg,37%) as a clear oil. LC (Method B): 1.372 min. MS(ESI) calcd forC₁₁H₁₂N₂O [M+H]⁺ m/z 187.0866. found 187.0898. ¹H NMR (400 MHz, acetone)ppm 8.87 (d, J=5.1 Hz, 2H) 8.47-8.55 (m, 1H) 8.37 (dt, J=7.4, 1.6 Hz,1H) 7.42-7.56 (m, 2H) 7.38 (t, J=4.7 Hz, 1H) 4.68-4.79 (m, 2H) 4.31 (t,J=5.9 Hz, 1H).

Example 32-Methoxy-6-(6-methoxy-4-((3-(pyrimidin-2-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, benzene was added to6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 30 mg, 0.095 mmol) and the mixture was sonificated for 30sec. and concentrated in vacuo to remove traces of water in the startingmaterial. Triphenylphosphine (62 mg, 0.236 mmol) was added and themixture was dried under high vacuum for 10 min.(3-(Pyrimidin-2-yl)phenyl)methanol (Example 4A, 50 mg, 0.269 mmol) andTHF (1.5 mL) were added and the mixture was sonificated for 5 min.Diisopropyl azodicarboxylate (0.045 ml, 0.231 mmol) in THF (1 mL) wasadded dropwise over 5 min. and the yellow solution was sonificated for30 min. and stirred over weekend at room temperature. The reactionmixture was then diluted in CH₂Cl₂, washed once with sat. NaHCO₃, oncewith brine, dried over anh. Na₂SO₄ and concentrated. The residue waspurified on ISCO using a REDISEP® Gold 12 g column (CH₂Cl₂/EtOAc). Thematerial (92% purity) was dissolved in DMF and purified on areverse-phase ZORBAX® SB-C18 column 21.2×100 mm and was eluted withMeOH-water-0.1% TFA with a gradient of 50% to 100% MeOH over 6 minutes.The fractions were collected, concentrated in vacuo and lyophilized inACN/water to give the title material (20 mg, 44%) as a yellowish solid.LC (Method B): 2.384 min. MS(ESI) calcd for C₂₅H₂₀N₅O₄S [M+H]⁺ m/z486.1231. found 486.1251. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.93 (d, J=5.1Hz, 2H) 8.50-8.60 (m, 1H) 8.33-8.42 (m, 2H) 7.65-7.73 (m, 1H) 7.59 (t,J=7.6 Hz, 1H) 7.47 (t, J=4.7 Hz, 1H) 7.00 (d, J=0.8 Hz, 1H) 6.84 (dd,J=1.8, 1.0 Hz, 1H) 6.56 (d, J=1.6 Hz, 1H) 5.38 (s, 2H) 4.20 (s, 3H) 3.79(s, 3H).

Preparation of Benzylic Alcohols

The following benzylic alcohols were prepared according to the proceduredescribed in Example 3A using (3-(hydroxymethyl)phenyl)boronic acid andthe corresponding bromides or iodides and were employed in preparingcompounds of the Examples as indicated.

Structure (Employed in HPLC preparation of Calc. Calc. LCMS Retentioncompound as [M + H]⁺ [M + H]⁺ − LCMS [M + H]⁺ − Time (Min)/ indicated)Formula m/z H₂O m/z [M + H]⁺ m/z H₂O m/z Method NMR

C₁₂H₁₀FNO 204.0819 204.0859 1.617/B ¹H NMR (400 MHz, acetone) δ ppm8.44-8.54 (m, 1 H) 8.16-8.29 (m, 1 H) 7.63-7.73 (m, 1 H) 7.53-7.61 (m, 1H) 7.38-7.52 (m, 2 H) 7.18 (ddd, J = 8.6, 3.1, 0.8 Hz, 1 H)4.64- 4.79(m, 2 H) 4.31 (t, J = 5.9 Hz, 1 H)

C₁₅H₁₇O₂ 229.1223 211.1118 229.1247 211.1148 1.996/B ¹H NMR (400 MHz,acetone) δ ppm 7.28-7.40 (m, 3 H) 7.17 (dt, J = 7.2, 1.5 Hz, 1 H) 7.12(d, J = 8.2 Hz, 1 H) 6.85 (d, J = 2.7 Hz, 1 H) 6.81 (dd, J = 8.6, 2.7Hz, 1 H) 4.61-4.74 (m, 2 H) 4.24 (t, J = 5.9 Hz, 1 H) 3.81 (s, 3 H) 2.23(s, 3 H)

C₁₁H₁₀OS 191.0525 173.0420 191.0533 173.0433 1.849/B ¹H NMR (400 MHz,acetone) δ ppm 7.72 (dd, J = 2.9, 1.4 Hz, 1 H) 7.70 (dt, J = 2.1, 1.1Hz, 1 H) 7.56 (dd, J = 5.1, 2.7 Hz, 1 H) 7.54-7.60 (m, 1 H) 7.52 (dd, J= 5.0, 1.6 Hz, 1 H) 7.37 (t, J = 7.6 Hz, 1 H) 7.27-7.32 (m, 1 H)4.62-4.72 (m, 2 H) 4.25 (t, J = 5.9 Hz, 1 H)

C₁₁H₁₂N₂O 189.1022 189.1049 1.439/B ¹H NMR (400 MHz, acetone) δ ppm 7.95(s, 1 H) 7.77 (d, J = 0.8 Hz, 1 H) 7.51-7.60 (m, 1 H) 7.43 (dt, J = 7.4,1.8 Hz, 1 H) 7.29 (t, J = 7.6 Hz, 1 H) 7.14-7.23 (m, 1 H) 4.58-4.68 (m,2 H) 4.20 (t, J = 5.9 Hz, 1 H) 3.90 (s, 3 H)

C₁₅H₁₂OS 241.0682 223.0576 241.0682 223.058 2.117/B ¹H NMR (400 MHz,acetone) δ ppm 7.99-8.07 (m, 1 H) 7.90-7.98 (m, 1 H) 7.60-7.70 (m, 2 H)7.40-7.55 (m, 5 H) 4.74 (d, J = 5.9 Hz, 2 H) 4.29 (t, J = 5.9 Hz, 1 H)

C₁₃H₁₀N₂O 211.0866 211.0882 1.561/B ¹H NMR (400 MHz, acetone) δ ppm 9.05(dd, J = 2.3, 0.8 Hz, 1H) 8.31 (dd, J = 7.8, 2.3 Hz, 1H) 8.02 (dd, J =8.0, 1.0 Hz, 1H) 7.76-7.85 (m, 1H) 7.62-7.74 (m, 1H) 7.44-7.58 (m, 2H)4.75 (d, J = 5.9 Hz, 2H) 4.35 (t, J = 5.7 Hz, 1H)

C₁₂H₁₀FNO 204.0819 204.0836 1.561/B ¹H NMR (400 MHz, acetone) δ ppm 8.57(d, J = 2.7 Hz, 1H) 8.06-8.12 (m, 1H) 7.97-8.05 (m, 1H) 7.89- 7.97 (m,1H) 7.62-7.76 (m, 1H) 7.37-7.50 (m, 2H) 4.72 (d, J = 5.9 Hz, 2H) 4.27(t, J = 5.9 Hz, 1H)

C₁₂H₁₁NO 186.0913 186.092  0.937/B ¹H NMR (400 MHz, acetone) δ ppm 8.87(dd, J = 2.3, 0.8 Hz, 1H) 8.57 (dd, J = 4.9, 1.8 Hz, 1H) 8.02 (dq, J =7.8, 1.3 Hz, 1H) 7.64-7.73 (m, 1H) 7.58 (dt, J = 7.6, 1.7 Hz, 1H) 7.37-7.52 (m, 3H) 4.73 (d, J = 6.3 Hz, 2H) 4.29 (t, J = 5.9 Hz, 1H)

C₁₃H₁₀F₂O 203.0667 203.0655 1.974/B ¹H NMR (400 MHz, acetone) δ ppm7.51-7.62 (m, 2H) 7.33-7.48 (m, 3 H) 7.05-7.20 (m, 2H) 4.71 (d, J = 6.3Hz, 2 H) 4.27 (t, J = 5.9 Hz, 1H)

C₁₄H₁₁F₃O 235.0730 235.0720 2.110/B ¹H NMR (400 MHz, acetone) δ ppm 7.89(m, J = 8.6 Hz, 2H) 7.81 (m, J = 8.6 Hz, 2H) 7.73 (s, 1H) 7.56- 7.64 (m,1H) 7.38-7.52 (m, 2H) 4.73 (d, J = 5.5 Hz, 2H) 4.31 (t, J = 5.7 Hz, 1H)

C₁₄H₁₂O₃ 229.0859 211.0754 229.0847 211.0749 1.869/B ¹H NMR (400 MHz,acetone) δ ppm 7.59 (s, 1H) 7.42-7.50 (m, 1H) 7.38 (t, J = 7.6 Hz, 1 H)7.27-7.34 (m, 1H) 7.07-7.20 (m, 2H) 6.88-6.98 (m, 1H) 6.04 (s, 2H) 4.69(d, J = 5.9 Hz, 2H) 4.21 (t, J = 5.9 Hz, 1H)

C₁₃H₁₄N₂O₃ 247.1077 247.109  1.543/B ¹H NMR (400 MHz, acetone) δ ppm8.30 (s, 1H) 7.50-7.58 (m, 1H) 7.31- 7.47 (m, 3H) 4.68 (d, J = 5.5 Hz,2H) 4.23 (t, J = 5.9 Hz, 1H) 3.99 (s, 3H) 3.98 (s, 3H)

C₁₃H₁₀N₂OS 243.0587 243.0595 1.916/B ¹H NMR (400 MHz, acetone) δ ppm8.26 (dd, J = 1.6, 0.8 Hz, 1H) 8.02- 8.19 (m, 2H) 7.85 (s, 1H) 7.73 (dt,J = 7.3, 1.6 Hz, 1H) 7.40-7.60 (m, 2 H) 4.77 (d, J = 5.9 Hz, 2H) 4.33(t, J = 5.9 Hz, 1H)

C₁₄H₁₂N₂O 225.1022 225.1038 1.010/B ¹H NMR (400 MHz, acetone) δ ppm 8.55(dt, J = 7.0, 1.2 Hz, 1H) 7.69 (s, 1H) 7.66-7.68 (m, 1H) 7.60 (dt, J =9.0, 1.2 Hz, 1H) 7.49-7.56 (m, 2H) 7.42-7.46 (m, 1H) 7.28 (ddd, J = 9.0,6.6, 1.2 Hz, 1H) 6.94 (td, J = 6.8, 1.2 Hz, 1H) 4.74 (d, J = 5.9 Hz, 2H)4.35 (t, J = 5.9 Hz, 1H)

C₁₄H₁₃N₂O 225.1022 225.1055 1.076/B ¹H NMR (400 MHz, acetone) δ ppm 8.79(dd, J = 1.8, 1.0 Hz, 1H) 7.87- 7.98 (m, 1H) 7.67-7.73 (m, 1H) 7.51-7.65(m, 4H) 7.45 (t, J = 7.6 Hz, 1H) 7.37-7.42 (m, 1H) 4.73 (d, J = 5.9 Hz,2H) 4.29 (t, J = 5.9 Hz, 1H)

C₁₃H₁₁N₃O 226.0975 226.0996 1.129/B ¹H NMR (400 MHz, DMSO-d₆) ppm 9.26(d, J = 0.8 Hz, 1H) 8.86-8.98 (m, 1H) 7.87 (dt, J = 9.4, 1.0 Hz, 1H)7.74 (dd, J = 9.6, 1.8 Hz, 1H) 7.65- 7.70 (m, 1H) 7.59 (dq, J = 7.8, 1.0Hz, 1H) 7.48 (t, J = 7.6 Hz, 1H) 7.33- 7.43 (m, 1H) 5.30 (br. s., 1H)4.59 (s, 2H)

C₁₃H₁₃NO₂ 216.1019 216.1048 1.764/B ¹H NMR (400 MHz, acetone) δ ppm 8.12(s, 1H) 7.97-8.05 (m, 1H) 7.75 (t, J = 7.8 Hz, 1H) 7.51 (d, J = 7.4 Hz,1H) 7.38-7.47 (m, 2H) 6.72 (d, J = 8.2 Hz, 1H) 4.72 (d, J = 5.9 Hz, 2H)4.25 (t, J = 5.9 Hz, 1H) 4.00 (s, 3H)

C₁₃H₁₃NO 200.1070 200.1091 0.992/B ¹H NMR (400 MHz, acetone) δ ppm8.43-8.54 (m, 1H) 8.07-8.15 (m, 1 H) 7.96 (dt, J = 6.7, 1.9 Hz, 1H) 7.81(d, J = 8.6 Hz, 1H) 7.60-7.73 (m, 1H) 7.34-7.49 (m, 2H) 4.71 (d, J = 5.9Hz, 2H) 4.24 (t, J = 5.9 Hz, 1H) 2.36 (s, 3H)

C₁₃H₁₃NO 200.1070 200.1087 0.998/B ¹H NMR (400 MHz, acetone) δ ppm 8.50(d, J = 5.9 Hz, 1H) 7.75 (s, 1H) 7.58-7.67 (m, 1H) 7.52 (s, 1H) 7.40-7.49 (m, 3H) 4.73 (d, J = 5.9 Hz, 2H) 4.32 (t, J = 5.7 Hz, 1H) 2.55 (s,3H)

C₁₃H₁₀N₂O 211.0866 211.0881 1.391/B ¹H NMR (400 MHz, acetone) δ ppm 8.75(dd, J = 4.7, 1.6 Hz, 1H) 8.02- 8.14 (m, 1H) 7.80 (dd, J = 8.6, 4.7 Hz,1H) 7.61-7.67 (m, 1H) 7.51-7.58 (m, 3H) 4.75 (d, J = 5.9 Hz, 2H) 4.38(t, J = 5.9 Hz, 1H)

C₁₄H₁₁NO 210.0913 210.0925 1.741/B ¹H NMR (400 MHz, acetone) δ ppm7.84-7.92 (m, 4H) 7.72-7.76 (m, 1H) 7.62 (dt, J = 7.0, 2.0 Hz, 1H) 7.43-7.51 (m, 2H) 4.73 (d, J = 5.9 Hz, 2H) 4.30 (t, J = 5.9 Hz, 1H)

C₁₄H₁₀FNO 228.0929 228.0819 1.800/B ¹H NMR (400 MHz, acetone) δ ppm7.89-7.96 (m, 1H) 7.71-7.80 (m, 3H) 7.66 (td, J = 3.5, 1.6 Hz, 1H) 7.46-7.52 (m, 2H) 4.74 (d, J = 5.9 Hz, 2H) 4.32 (t, J = 5.7 Hz, 1H)

C₁₂H₁₀N₂O₃ 231.0764 231.0767 1.507/B ¹H NMR (400 MHz, acetone) δ ppm8.94 (dd, J = 2.3, 0.8 Hz, 1H) 8.49 (dd, J = 8.4, 2.5 Hz, 1H) 8.39 (dd,J = 8.6, 0.8 Hz, 1H) 7.82-7.85 (m, 1H) 7.70-7.76 (m, 1H) 7.52-7.58 (m,2H) 4.76 (d, J = 5.4 Hz, 2H) 4.36 (t, J = 5.7 Hz, 1H)

C₁₅H₁₄O₃ 243.1027 243.1013 1.854/B ¹H NMR (400 MHz, acetone) δ ppm 7.58(dt, J = 2.4, 0.9 Hz, 1H) 7.43- 7.47 (m, 1H) 7.37 (t, J = 7.6 Hz, 1H)7.28-7.32 (m, 1H) 7.11-7.14 (m, 2H) 6.89-6.92 (m, 1H) 4.69 (d, J = 5.9Hz, 2H) 4.30 (s, 4H) 4.20 (t, J = 5.9 Hz, 1H)

C₁₃H₁₂FNO 218.0976 218.1007 1.604/B ¹H NMR (400 MHz, acetone) δ ppm 8.07(s, 1H) 7.93 (dt, J = 6.4, 2.3 Hz, 1H) 7.80 (dd, J = 8.6, 3.5 Hz, 1H)7.57 (t, J = 8.8 Hz, 1H) 7.37-7.46 (m, 2H) 4.72 (d, J = 5.8 Hz, 2H) 4.25(t, J = 5.9 Hz, 1H) 2.54 (d, J = 3.1 Hz, 3H)

C₁₂H₉F₂NO 222.0725 222.0747 1.672/B ¹H NMR (400 MHz, acetone) δ ppm8.51-8.56 (m, 1H) 7.93-7.98 (m, 1H) 7.81 (ddt, J = 5.2, 3.7, 2.0, 2.0Hz, 1H) 7.68-7.77 (m, 1H) 7.43- 7.50 (m, 2H) 4.73 (d, J = 5.8 Hz, 2H)4.30 (t, J = 5.9 Hz, 1H)

C₁₄H₁₆N₂O₂ 205.0772 205.0873 1.837/B ¹H NMR (400 MHz, acetone) δ ppm8.81 (s, 2 H) 7.65 (s, 1H) 7.51-7.58 (m, 1H) 7.46 (t, J = 7.5 Hz, 1H)7.39- 7.43 (m, 1H) 4.71 (d, J = 5.9 Hz, 2H) 4.33 (t, J = 6.7 Hz, 2H)4.27 (t, J = 6.1 Hz, 1H) 1.81 (sxt, J = 7.1 Hz, 2H) 1.02 (t, J = 7.4 Hz,3H)

C₁₂H₁₀ClNO 220.0524 220.0545 1.759/B ¹H NMR (400 MHz, acetone) δ ppm8.65 (d, J = 2.3 Hz, 1 H) 8.12 (s, 1H) 7.94-8.01 (m, 2H) 7.89-7.94 (m,1H) 7.42-7.49 (m, 2H) 4.69-4.76 (m, 2H) 4.28 (t, J = 5.9 Hz, 1H)

C₁₃H₁₀N₂O 211.0866 211.0875 1.515/B ¹H NMR (400 MHz, acetone) δ ppm 9.03(dd, J = 2.2, 1.0 Hz, 1H) 8.26- 8.31 (m, 1H) 8.20-8.24 (m, 1H) 8.17 (dd,J = 8.4, 1.0 Hz, 1H) 8.04- 8.10 (m, 1H) 7.47-7.56 (m, 2H) 4.72-4.78 (m,2H) 4.34 (t, J = 5.9 Hz, 1H)

C₁₃H₁₃NO₂ 216.1019 216.1052 1.628/B ¹H NMR (400 MHz, CDCl₃) δ ppm 8.40(d, J = 2.7 Hz, 1H), 7.81 (dd, J = 8.4, 2.2 Hz, 1H), 7.55 (s, 1H),7.42-7.51 (m, 2H), 7.37 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H),4.79 (d, J = 5.9 Hz, 2H), 4.00 (s, 3H), 1.70 (t, J = 5.9 Hz, 1H)

C₁₂H₁₁NO₃ 218.0812 218.0830 1.299/B ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31(s, 1H) 7.82 (br. s., 1H) 7.53-7.60 (m, 2H) 7.50 (d, J = 7.8 Hz, 1H)7.43 (br. s., 1H) 7.37 (t, J = 7.8 Hz, 1H) 7.25 (d, J = 7.4 Hz, 1H) 5.22(br. s., 1H) 4.53 (s, 2H)

C₁₃H₁₂FNO 218.0976 218.1002 1.725/B ¹H NMR (400 MHz, acetone) δ ppm8.25-8.31 (m, 1H) 8.01-8.09 (m, 1H) 7.66 (s, 1H) 7.55 (dt, J = 7.3, 1.6Hz, 1H) 7.45 (t, J = 7.3 Hz, 1H) 7.40- 7.43 (m, 1 H) 4.72 (d, J = 5.9Hz, 2H) 4.27 (t, J = 5.9 Hz, 1H) 2.32-2.38 (m, 3H)

C₁₃H₁₂FNO 218.0976 218.1005 1.654/B ¹H NMR (400 MHz, acetone) δ ppm 7.93(dd, J = 10.6, 7.4 Hz, 1H) 7.56- 7.62 (m, 1H) 7.38-7.51 (m, 3H)7.25-7.31 (m, 1H) 4.71 (d, J = 5.9 Hz, 2H) 4.28 (t, J = 5.7 Hz, 1H) 2.49(s, 3H)

C₁₃H₁₃NO₂ 216.1019 216.1059 1.099/B ¹H NMR (400 MHz, acetone) δ ppm8.34-8.38 (m, 1H) 8.04-8.08 (m, 1H) 7.91 (dt, J = 7.1, 1.7 Hz, 1H) 7.84-7.88 (m, 1H) 7.33-7.46 (m, 3H) 4.71 (d, J = 5.9 Hz, 2H) 4.21 (t, J = 5.9Hz, 1H) 3.93 (s, 3H)

C₁₂H₉N₃O 212.0817 1.546/B ¹H NMR (400 MHz, acetone) δ ppm 9.40 (s, 1H)9.16 (s, 1H) 8.25-8.30 (m, 1H) 8.14 (dt, J = 7.4, 1.8 Hz, 1H) 7.53-7.63(m, 2H) 4.77 (d, J = 6.3 Hz, 2H) 4.43 (t, J = 5.9 Hz, 1H)

C₁₃H₁₀F₃NO 254.0787 254.0802 1.857/B ¹H NMR (400 MHz, acetone) δ ppm8.97-9.03 (m, 1H) 8.15-8.25 (m, 3H) 8.05-8.10 (m, 1H) 7.46-7.54 (m, 2H)4.75 (d, J = 5.9 Hz, 2H) 4.35 (t, J = 5.9 Hz, 1H)

C₁₂H₁₀FNO 204.0819 204.0834 1.447/B ¹H NMR (400 MHz, acetone) δ ppm8.51-8.57 (m, 1H) 7.99-8.04 (m, 1H) 7.87 (ddt, J = 5.3, 3.6, 2.0, 2.0Hz, 1H) 7.71 (ddd, J = 11.6, 8.3, 1.5 Hz, 1H) 7.41-7.49 (m, 3H) 4.73 (d,J = 5.9 Hz, 2H) 4.32 (t, J = 5.9 Hz, 1H)

C₁₃H₁₀N₂O 211.0883 211.0886 1.363/B ¹H NMR (400 MHz, acetone) δ ppm 8.89(d, J = 0.8 Hz, 1H) 8.82 (d, J = 5.1 Hz, 1H) 7.86 (dd, J = 4.9, 1.0 Hz,1H) 7.64-7.67 (m, 1H) 7.53-7.58 (m, 3H) 4.76 (d, J = 5.9 Hz, 2H) 4.37(t, J = 5.9 Hz, 1H)

C₁₂H₁₀FNO 204.0819 204.0833 1.497/B ¹H NMR (400 MHz, acetone) δ ppm 8.22(dt, J = 4.6, 1.8 Hz, 1H) 8.06 (ddd, J = 10.2, 7.4, 2.0 Hz, 1H) 7.60-7.64 (m, 1H) 7.41-7.53 (m, 4H) 4.72 (d, J = 5.5 Hz, 2H) 4.30 (t, J = 5.9Hz, 1H)

C₁₀H₉NOS 192.0478 192.0488 1.445/B ¹H NMR (400 MHz, acetone) δ ppm 9.17(s, 1H) 8.94 (s, 1H) 7.74-7.79 (m, 1H) 7.62-7.67 (m, 1H) 7.42 (t, J =7.5 Hz, 1H) 7.35-7.39 (m, 1H) 4.70 (d, J = 5.9 Hz, 2H) 4.26 (t, J = 5.9Hz, 1H)

C₁₂H₁₂N₂O₂ 217.0972 217.0977 1.477/B ¹H NMR (400 MHz, acetone) δ ppm8.84 (s, 2H) 7.65-7.69 (m, 1H) 7.53- 7.59 (m, 1H) 7.45-7.50 (m, 1H)7.41-7.45 (m, 1H) 4.72 (d, J = 5.9 Hz, 2H) 4.29 (t, J = 5.9 Hz, 1H) 4.00(s, 3H)

C₁₄H₁₆N₂O 229.1335 229.1350 1.122/B ¹H NMR (400 MHz, acetone) δ ppm 8.42(dd, J = 2.3, 0.8 Hz, 1H) 7.79 (dd, J = 9.0, 2.8 Hz, 1H) 7.58 (dt, J =2.1, 1.1 Hz, 1H) 7.43-7.49 (m, 1H) 7.37 (t, J = 7.6 Hz, 1H) 7.26- 7.32(m, 1H) 6.70 (dd, J = 9.0, 0.8 Hz, 1H) 4.68 (d, J = 6.2 Hz, 2H) 4.19 (t,J = 5.9 Hz, 1H) 3.11 (s, 6H)

C₁₂H₉ClFNO 238.0429 238.0452 1.821/B ¹H NMR (400 MHz, acetone) δ ppm8.57 (dd, J = 2.0, 1.2 Hz, 1H) 7.98- 8.02 (m, 1H) 7.92 (dd, J = 11.0,2.0 Hz, 1H) 7.81-7.87 (m, 1H) 7.46- 7.52 (m, 2H) 4.71-4.76 (m, 2H) 4.32(t, J = 5.9 Hz, 1H)

C₁₄H₁₅NO₂ 230.1176 230.1207 1.487/B ¹H NMR (400 MHz, acetone) δ ppm 7.94(s, 1H) 7.32-7.45 (m, 3H) 7.19- 7.24 (m, 1H) 6.69 (quin, J = 0.8 Hz, 1H)4.70 (d, J = 6.3 Hz, 2H) 4.24 (t, J = 5.9 Hz, 1H) 3.90 (s, 3H) 2.23 (d,J = 0.8 Hz, 3H)

C₁₃H₁₂ClNO 234.068 234.0713 1.665/B ¹H NMR (400 MHz, acetone) δ ppm8.45-8.48 (m, 1H) 7.78 (dq, J = 2.4, 0.8 Hz, 1H) 7.54-7.57 (m, 1H) 7.43(d, J = 1.6 Hz, 3H) 4.71 (d, J = 5.9 Hz, 2H) 4.26 (t, J = 5.9 Hz, 1H)2.38 (s, 3H)

C₁₂H₁₂N₂O₂ 217.0972 217.0991 1.647/B ¹H NMR (400 MHz, acetone) δ ppm8.69 (d, J = 1.2 Hz, 1H) 8.29 (d, J = 1.6 Hz, 1H) 8.03-8.07 (m, 1H) 7.90(dt, J = 7.3, 1.8 Hz, 1H) 7.39-7.48 (m, 2H) 4.72 (d, J = 6.3 Hz, 2H)4.25 (t, J = 5.9 Hz, 1H) 4.00 (s, 3H)

C₁₂H₉Cl₂NO 254.1034 254.0157 1.872/B ¹H NMR (400 MHz, acetone) δ ppm8.63 (d, J = 2.3 Hz, 1H) 8.09-8.13 (m, 1H) 7.70-7.75 (m, 1H) 7.58- 7.63(m, 1H) 7.41-7.50 (m, 2H) 4.72 (d, J = 5.9 Hz, 2H) 4.28 (t, J = 5.9 Hz,1H)

C₁₂H₁₀FNO 204.0819 204.0838 1.534/B ¹H NMR (400 MHz, acetone) δ ppm8.25-8.31 (m, 1H) 7.79-7.83 (m, 1H) 7.66-7.73 (m, 1H) 7.60-7.66 (m, 1H)7.47-7.55 (m, 2H) 7.34- 7.38 (m, 1H) 4.71-4.76 (m, 2H) 4.32 (t, J = 5.9Hz, 1H)

C₁₂H₁₀ClNO 220.0524 220.0545 1.658/B ¹H NMR (400 MHz, acetone) δ ppm8.68 (dd, J = 2.7, 0.8 Hz, 1H) 8.10 (dd, J = 8.4, 2.5 Hz, 1H) 7.68-7.72(m, 1H) 7.57-7.60 (m, 1H) 7.54 (dd, J = 8.2, 0.8 Hz, 1H) 7.43-7.50 (m,2H) 4.73 (d, J = 6.3 Hz, 2H) 4.29 (t, J = 5.7 Hz, 1H)

C₁₇H₁₈N₂O₃ 299.1390 299.1421 1.365/B ¹H NMR (400 MHz, acetone) δ ppm8.86 (dd, J = 2.3, 1.2 Hz, 1H) 8.17 (dd, J = 8.2, 2.3 Hz, 1H) 7.72-7.77(m, 2H) 7.63 (dt, J = 7.0, 1.8 Hz, 1H) 7.43-7.53 (m, 2H) 4.74 (d, J =6.3 Hz, 2H) 4.30 (t, J = 5.9 Hz, 1H) 3.73 (s, 4 H) 3.60-3.71 (m, 4H)

C₁₃H₁₄N₂O₃ 247.1077 247.1095 1.300/B ¹H NMR (400 MHz, acetone) δ ppm8.13 (d, J = 1.2 Hz, 1H) 8.06 (d, J = 1.2 Hz, 1H) 7.87-7.91 (m, 1H)7.73- 7.79 (m, 1H) 7.39 (t, J = 7.6 Hz, 1H) 7.29-7.35 (m, 1H) 5.37 (s,2H) 4.69 (d, J = 6.3 Hz, 2H) 4.24 (t, J = 5.7 Hz, 1H) 3.42 (s, 3H)

C₁₇H₁₉NO₃ 286.14 230.2   [M + H]⁺− tBu 1.612/B ¹H NMR (400 MHz, acetone)δ ppm 8.96 (dd, J = 2.3, 0.8 Hz, 1H) 8.19 (dd, J = 8.2, 2.3 Hz, 1H) 8.11(dd, J = 8.2, 0.8 Hz, 1H) 7.74-7.79 (m, 1H) 7.65 (dt, J = 7.2, 1.7 Hz,1H) 7.45- 7.55 (m, 2H) 4.72-4.77 (m, 2H) 4.32 (t, J = 5.9 Hz, 1H) 1.62(s, 9H)

C₂₂H₂₃NO₃ 350.18 350.2   1.784/B ¹H NMR (400 MHz, acetone) δ ppm8.62-8.68 (m, 1H) 8.12-8.18 (m, 1H) 7.97-8.03 (m, 1H) 7.94 (dd, J = 8.2,0.8 Hz, 1H) 7.81-7.90 (m, 1H) 7.39-7.48 (m, 2H) 7.22-7.31 (m, 2H)6.86-6.94 (m, 2H) 4.71- 4.76 (m, 2H) 4.66 (q, J = 6.3 Hz, 1H) 4.34-4.44(m, 2H) 4.26 (t, J = 5.9 Hz, 1H) 3.79 (s, 3H) 1.49 (d, J = 6.7 Hz, 3H)

Examples 4 to 61

The following additional Examples have been prepared, isolated andcharacterized using the method disclosed in Examples 1 to 3 employingthe appropriate benzylic alcohol set out hereinbefore.

HPLC Retention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 4

C₂₉H₂₁N₃O₄S 540.1055 2.688/B 540.1046 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.34-8.43 (m, 1H) 7.99 (d, J = 7.4 Hz, 1H) 7.92 (s, 2H) 7.83-7.90 (m, 1H) 7.73- 7.83 (m, 1H) 7.54 (d, J = 4.3 Hz, 2H) 7.39 (quint, J = 7.3,7.3, 7.3, 7.3, 1.4, 1.4 Hz, 2H) 7.03 (s, 1H) 6.80-6.91 (m, 1H) 6.49-6.64(m, 1H) 5.35 (s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 5

C₂₆H₁₂N₄O₂S₃ 503.1384 2.396/B 503.1399 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.47-7.57 (m, 3H) 7.36 (ddd, J = 5.2, 3.6, 1.8 Hz, 1H) 6.98(d, J = 0.8 Hz, 1H) 6.79-6.88 (m, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.32 (s,2H) 4.20 (s, 3H) 3.79 (s, 3H) 2.39 (s, 3H) 2.22 (s, 3H) 6

C₂₅H₂₀N₃O₅S 474.1118 2.411/B 474.113 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.17-8.27 (m, 1H) 7.70- 7.81 (m, 2H) 7.60 (d, J = 7.0 Hz,1H) 7.33- 7.48 (m, 2H) 6.92-7.04 (m, 2H) 6.83 (s, 1 H) 6.56 (s, 1H) 5.27(s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 7

C₂₆H₁₉FN₄O₄S 503.1184 2.400/B 503.1205 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.58 (d, J = 2.7 Hz, 1H) 8.38 (s, 1H) 8.32 (td, J = 8.2, 2.7 Hz, 1H)7.81-7.93 (m, 1H) 7.71 (dt, J = 6.9, 2.1 Hz, 1H) 7.49- 7.63 (m, 2H) 7.31(dd, J = 8.6, 3.5 Hz, 1H) 7.01 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0,0.8 Hz, 1H) 6.57 (d, J = 2.0 Hz, 1H) 5.33 (s, 2H) 4.20 (s, 3H) 3.80 (s,1H) 8

C₂₉H₂₅N₃O₅S 528.1588 2.573/B 528.1607 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.45-7.49 (m, 2H) 7.42 (s, 1H) 7.27 (ddd, J = 5.3, 3.5, 1.8Hz, 1H) 7.14 (d, J = 8.6 Hz, 1H) 6.96 (d, J = 0.8 Hz, 1H) 6.88 (d, J =2.7 Hz, 1H) 6.80-6.86 (m, 2H) 6.55 (d, J = 2.0 Hz, 1H) 5.31 (s, 2H) 4.20(s, 3H) 3.79 (s, 3H) 3.77 (s, 3H) 2.20 (s, 3H) 9

C₂₅H₁₉N₃O₄S₂ 490.089 2.505/B 490.0888 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.89-7.95 (m, 1H) 7.85 (s, 1H) 7.70 (dt, J = 6.5, 2.1 Hz,1H) 7.66 (ddd, J = 5.0, 3.0, 1.0 Hz, 1H) 7.58 (dt, J = 5.1, 1.2 Hz, 1H)7.37-7.51 (m, 2H) 7.00 (s, 1H) 6.83 (s, 1H) 6.56 (d, J = 0.8 Hz, 1H)5.29 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 10

C₂₅H₂₁N₅O₄S 488.1387 2.344/B 488.1388 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.16 (s, 1H) 7.87 (s, 1H) 7.69 (s, 1H) 7.54 (d, J = 7.4 Hz,1H) 7.39 (t, J = 7.6 Hz, 1H) 7.28-7.35 (m, 1H) 7.00 (s, 1H) 6.83 (s, 1H)6.55 (d, J = 2.0 Hz, 1H) 5.25 (s, 2H) 4.20 (s, 3H) 3.86 (s, 3H) 3.79 (s,3H) 11

C₂₅H₂₀N₄O₄S₂ 505.0999 2.411/B 505.0996 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.09 (s, 1H) 7.97 (s, 1H) 7.91 (t, J = 4.5 Hz, 1H) 7.48 (d,J = 5.l Hz, 2H) 7.00 (s, 1H) 6.83 (s, 1H) 6.56 (s, 1H) 5.31 (s, 2H) 4.20(s, 3H) 3.80 (s, 3H) 2.72 (s, 3H) 12

C₂₉H₂₁N₃O₄S₂ 450.1046 2.652/B 540.1073 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.02-8.14 (m, 1H) 7.87 (s, 1H) 7.81-7.86 (m, 1H) 7.74 (s,1H) 7.53- 7.63 (m, 3H) 7.35-7.48 (m, 2H) 7.00 (s, 1H) 6.84 (d, J = 0.8Hz, 1H) 6.58 (d, J = 1.6 Hz, 1H) 5.38 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H)13

C₂₇H₁₉N₅O₄S 510.1231 2.364/B 510.1108 ¹H NMR (400 MHz, acetone) ppm 9.11(dd, J = 2.3, 0.8 Hz, 1H) 8.37 (dd, J = 8.3, 2.4 Hz, 1H) 8.10 (s, 1H)8.01-8.09 (m, 2H) 7.81 (dt, J = 7.8, 1.4 Hz, 1H) 7.69- 7.76 (m, 1H) 7.64(t, J = 7.5 Hz, 1H) 7.05 (d, J = 0.8 Hz, 1H) 6.77 (dd, J = 2.0, 0.8 Hz,1H) 6.56 (d, J = 2.0 Hz, 1H) 5.40 (s, 2H) 4.26 (s, 3H) 3.85 (s, 3H) 14

C₂₆H₁₉FN₄O₄S 503.1184 2.431/B 503.1222 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.67 (d, J = 3.1 Hz, 1H) 8.38 (s, 1H) 8.20 (s, 1H) 8.08 (dd, J = 8.6,4.3 Hz, 1H) 8.02 (d, J = 7.4 Hz, 1H) 7.84 (td, J = 8.8, 3.1 Hz, 1H) 7.56(td, J = 14.9, 7.4 Hz, 2H) 7.00 (s, 1H) 6.83 (s, 1H) 6.56 (s, 1H) 5.34(1H) 15

C₂₆H₂₀N₄O₄S 485.1278 2.149/B 485.1338 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.01- 9.10 (m, 1H) 8.66-8.78 (m, 1H) 8.42 (dd, J = 6.7, 3.9 Hz, 1 H)8.38 (s, 1H) 7.94 (s, 1H) 7.68-7.81 (m, 2H) 7.52-7.67 (m, 2H) 7.01 (s,1H) 6.84 (s, 1H) 6.58 (s, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 16

C₂₈H₂₀F₃N₃O₄S 552.1199 2.584/B 552.1246 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.93 (d, J = 7.8 Hz, 2H) 7.88 (s, 1H) 7.84 (d, J = 7.6 Hz,2H) 7.73 (d, J = 6.7 Hz, 1H) 7.50-7.64 (m, 2H) 7.00 (s, 1H) 6.84 (d, J =0.8 Hz, 1H) 6.57 (d, J = 1.2 Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.80 (s,3H) 17

C₂₇H₁₉F₂N₃O₄S 520.1137 2.540/B 520.1128 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.46-7.69 (m, 5H) 7.33-7.44 (m, 1H) 7.15-7.28 (m, 1H) 6.98(s, 1H) 6.84 (s, 1H) 6.56 (s, 1H) 5.32 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H)18

C₂₈H₂₁N₃O₆S 528.1224 2.538/B 528.1232 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.73 (s, 1H) 7.51-7.63 (m, 1H) 7.46 (d, J = 3.9 Hz, 2H)7.26 (s, 1H) 7.11- 7.21 (m, 1H) 6.95-7.04 (m, 2H) 6.83 (s, 1H) 6.56 (s,1H) 6.06 (s, 2H) 5.30 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 19

C₂₇H₂₃N₅O₆S 546.1442 2.395/B 546.1466 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.39 (s, 1H) 8.37 (s, 1H) 7.67 (s, 1H) 7.40- 7.57 (m, 3H) 6.99 (s, 1H)6.83 (s, 1H) 6.56 (s, 1H) 5.30 (s, 2H) 4.20 (s, 3H) 3.94 (s, 3H) 3.93(s, 3H) 3.79 (s, 3H) 20

C₂₇H₁₉N₅O₄S₂ 542.0951 2.605/B 542.0929 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.39 (dd, J = 1.8, 1.0 Hz, 1H) 8.37 (s, 1H) 8.20 (dd, J = 9.4, 0.8 Hz,1H) 8.12 (dd, J = 9.2, 1.8 Hz, 1H) 8.03 (s, 1H) 7.87 (dt, J = 7.0, 2.0Hz, 1H) 7.52-7.68 (m, 2H) 7.02 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0,0.8 Hz, 1H) 6.59 (d, J = 2.0 Hz, 1H) 5.37 (s, 2H) 4.20 (s, 3H) 3.80 (s,3H) 21

C₂₈H₂₁N₅O₄S 524.1387 2.032/B 524.1393 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.78 (dd, J = 6.8, 1.0 Hz, 1H) 8.39-8.45 (m, 1H) 8.37 (s, 1H) 8.03 (d, J= 9.0 Hz, 1H) 7.95 (t, J = 8.0 Hz, 1H) 7.88 (s, 1H) 7.64-7.79 (m, 3H)7.45 (td, J = 7.1, 1.0 Hz, 1H) 7.01 (s, 1H) 6.83-6.89 (m, 1H) 6.58 (d, J= 2.0 Hz, 1H) 5.39 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 22

C₂₇H₂₀N₆O₄S 525.1340 2.217/B 525.1351 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.32 (s, 1H) 8.96-9.05 (m, 1H) 8.32- 8.43 (m, 1H) 7.79-8.00 (m, 3H)7.67- 7.79 (m, 1H) 7.50-7.65 (m, 2H) 7.02 (s, 1H) 6.84 (s, 1H) 6.58 (s,1H) 5.34 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 23

C₂₈H₂₁N₅O₄S 524.1387 2.069/B 524.1411 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.32 (dd, J = 1.8, 1.0 Hz, 1H) 8.38 (s, 1H) 8.26-8.34 (m, 2H) 8.21 (d, J= 2.3 Hz, 1H) 8.06 (d, J = 9.4 Hz, 1H) 7.94 (s, 1H) 7.78 (dt, J = 6.5,2.2 Hz, 1H) 7.50-7.70 (m, 3H) 7.01 (d, J = 0.8 Hz, 1H) 6.85 (dd, J =1.8, 1.0 Hz, 1H) 6.58 (d, J = 1.6 Hz, 1H) 5.36 (s, 2H) 4.20 (s, 3H) 3.80(s, 3H) 24

C₂₇H₂₂N₄O₅S 515.1384 2.548/B 515.1382 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.21-8.30 (m, 1H) 8.06 (dt, J = 7.4, 1.6 Hz, 1H) 7.79 (t, J= 7.8 Hz, 1H) 7.48-7.62 (m, 3H) 7.00 (s, 1H) 6.83 (s, 1H) 6.79 (d, J =8.2 Hz, 1H) 6.58 (d, J = 2.0 Hz, 1H) 5.36 (s, 2H) 4.20 (s, 3H) 3.94 (s,3H) 3.79 (s, 3H) 25

C₂₇H₂₂N₄O₄S 499.1435 2.138/B 499.1456 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.46-8.56 (m, 1H) 8.38 (s, 1H) 8.21 (t, J = 1.6 Hz, 1H) 8.02 (dt, J =7.4, 1.6 Hz, 1H) 7.89 (d, J = 8.2 Hz, 1H) 7.71 (ddd, J = 8.2, 2.4, 0.8Hz, 1H) 7.45 26

C₂₇H₁₉N₅O₄S 510.1231 2.285/B 510.1244 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.79 (d, J = 4.7 Hz, 1H) 8.37 (s, 1H) 8.16 (dt, J = 8.0, 1.3 Hz, 1H)7.85 (dd, J = 8.0, 4.9 Hz, 1H) 7.82 (s, 1H) 7.59-7.72 (m, 3H) 7.03 (s,1H) 6.84 (s, 1H) 6.59 (s, 1H) 5.34 (s, 2H) 4.21 (s, 3H) 3.81 (s, 3H) 27

C₂₇H₂₂N₄O₄S 499.1435 2.058/B 499.1453 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.51 (d, J = 5.1 Hz, 1H) 8.37 (s, 1H) 7.92 (s, 1H) 7.76 (d, J = 7.8 Hz,1H) 7.46-7.68 (m, 4H) 7.00 (s, 1H) 6.83 (s, 1H) 6.57 (s, 1H) 5.34 (s,2H) 4.20 (s, 3H) 3.79 (s, 3H) 2.53 (s, 3H) 28

C₂₆H₁₉N₅O₆S 530.1140 2.355/B 530.1129 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.02-9.07 (m, 1H) 8.53-8.59 (m, 1H) 8.42 (d, J = 8.2 Hz, 1H) 8.38 (s,1H) 8.03 (s, 1H) 7.87 (d, J = 7.4 Hz, 1H) 7.59-7.71 (m, 2H) 7.02 (s, 1H)6.84 (s, 1H) 6.58 (s, 1H) 5.36 (s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 29

C₂₈H₂₀N₄O₄S 509.1278 2.433/B 509.1289 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.86-7.98 (m, 5H) 7.74 (d, J = 7.0 Hz, 1H) 7.52-7.63 (m,2H) 7.00 (s, 1H) 6.84 (s, 1H) 6.57 (s, 1H) 5.34 (s, 2H) 4.20 (s, 3H)3.79 (s, 3H) 30

C₂₈H₁₉FN₄O₄S 527.1184 2.446/B 527.1194 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.37 (s, 1H) 8.00-8.07 (m, 1H) 7.90- 7.98 (m, 2H) 7.79 (dd, J = 8.2, 1.2Hz, 2H) 7.54-7.66 (m, 2H) 7.01 (s, 1H) 6.84 (s, 1H) 6.57 (d, J = 1.6 Hz,1H) 5.33 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 31

C₂₉H₂₃N₃O₆S 543.1380 2.534/B 543.1380 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 7.72 (s, 1H) 7.53-7.59 (m, 1H) 7.42-7.47 (m, 2H) 7.12-7.18(m, 2H) 6.99 (s, 1H) 6.94 (d, J = 8.2 Hz, 1H) 6.81-6.84 (m, 1H) 6.55 (d,J = 1.2 Hz, 1H) 5.30 (s, 2H) 4.28 (s, 4H) 4.20 (s, 3H) 3.79 (s, 3H) 32

C₂₇H₂₁FN₄O₄S 517.1340 2.467/B 517.1355 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.18 (s, 1H) 8.00 (d, J = 7.4 Hz, 1H) 7.88 (dd, J = 7.8,3.5 Hz, 1H) 7.73 (t, J = 9.0 Hz, 1H) 7.49-7.60 (m, 2H) 7.00 (s, 1H) 6.84(s, 1H) 6.57 (s, 1H) 5.34 (s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 2.53 (d, J =2.3 Hz, 3H) 33

C₂₆H₁₈F₂N₄O₄S 521.1090 2.454/B 521.1101 ¹H NMR (400 MHz, DMSO-d₆) d ppm8.64-8.68 (m, 1H) 8.38 (s, 1H) 8.09 (ddd, J = 11.3, 9.0, 2.3 Hz, 1H)8.00-8.03 (m, 1H) 7.82-7.87 (m, 1H) 7.63 (dt, J = 7.7, 1.4 Hz, 1H) 7.58(t, J = 7.6 Hz, 1H) 6.98 (d, J = 0.8 Hz, 1H) 6.83 (dd, J = 1.6, 0.8 Hz,1H) 6.56 (d, J = 2.0 Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 34

C₂₇H₂₂N₄O₅S 515.1384 2.482/B 515.1386 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.50 (d, J = 2.1 Hz, 1H) 8.38 (s, 1H) 8.04 (dd, J = 8.6, 2.7 Hz, 1H)7.79 (s, 1H) 7.60- 7.68 (m, 1H) 7.48-7.55 (m, 2H) 7.00 (s, 1H) 6.93 (d,J = 8.6 Hz, 1H) 6.81-6.85 (m, 1H) 6.57 (d, J = 1.2 Hz, 1H) 5.32 (s, 2H)4.20 (s, 3H) 3.90 (s, 3H) 3.79 (s, 3H) 35

C₂₇H₁₉N₅O₄S 510.1231 2.399/B 510.1229 ¹H NMR (400 MHz, DMSO-d₆) ppm δ9.09-9.16 (m, 1H) 8.39-8.44 (m, 1H) 8.38 (s, 1H) 8.34 (s, 1H) 8.21-8.27(m, 1H) 8.15 (d, J = 8.2 Hz, 1H) 7.68 (d, J = 7.4 Hz, 1H) 7.60 (t, J =7.6 Hz, 1H) 7.00 (s, 1H) 6.84 (s, 1H) 6.57 (s, 1H) 5.36 (s, 2H) 4.20 (s,3H) 3.79 (s, 3H) 36

C₂₆H₁₉ClN₄O₄S 519.0888 2.529/B 519.0887 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.70-8.75 (m, 1H) 8.38 (s, 1H) 8.22- 8.26 (m, 1H) 8.00-8.08 (m, 3H)7.58- 7.64 (m, 1H) 7.55 (t, J = 7.7 Hz, 1H) 7.00 (s, 1H) 6.81-6.85 (m,1H) 6.56 (d, J = 1.6 Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 37

C₂₈H₂₅N₅O₅S 544.1649 2.511/B 544.1651 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.95 (s, 2 H) 8.38 (s, 1H) 7.88 (s, 1H) 7.67-7.76 (m, 1H) 7.51-7.61 (m,2H) 7.02 (s, 1H) 6.84 (s, 1H) 6.54-6.61 (m, 1H) 5.32 (s, 2H) 4.32 (t, J= 6.7 Hz, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 1.78 (sxt, J = 7.0 Hz, 2H) 0.99(t, J = 7.4 Hz, 3H) 38

C₂₇H₂₁FN₄O₄S 517.134 2.453/B 517.1355 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.37 (s, 2H) 8.19 (d, J = 9.8 Hz, 1H) 7.85 (s, 1H) 7.66-7.73 (m, 1H)7.50-7.60 (m, 2H) 7.01 (s, 1H) 6.84 (s, 1H) 6.54-6.59 (m, 1H) 5.32 (s,2H) 4.20 (s, 3H) 3.80 (s, 3H) 2.32 (s, 3H) 39

C₂₇H₂₁FN₄O₄S 517.134 2.413/B 517.1358 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.37 (s, 1H) 8.03 (dd, J = 10.4, 7.6 Hz, 1H) 7.74 (s, 1H) 7.50-7.61 (m,3H) 7.34 (d, J = 7.4 Hz, 1H) 6.99 (s, 1H) 6.84 (s, 1H) 6.57 (s, 1H) 5.32(s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 2.48 (s, 3H) 40

C₂₇H₂₂N₄O₅S 515.1384 2.245/B 515.1412 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.36-8.41 (m, 2H) 8.17 (s, 1H) 7.92- 8.01 (m, 2H) 7.46-7.55 (m, 3H) 6.99(s, 1H) 6.83 (s, 1H) 6.56 (s, 1H) 5.33 (s, 2H) 4.20 (s, 3H) 3.88 (s, 3H)3.79 (s, 3H) 41

C₂₆H₂₀N₄O₆S 517.1176 2.233/B 517.1206 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.36-8.37 (m, 1H) 7.84 (br. s., 1H) 7.79 (s, 1H) 7.63 (dt,J = 6.4, 2.1 Hz, 1H) 7.58 (d, J = 1.2 Hz, 1H) 7.41- 7.50 (m, 3H) 7.01(d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0, 0.8 Hz, 1H) 6.56 (d, J = 2.0 Hz,1H) 5.27 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 42

C₂₆H₁₈N₆O₄S 511.1183 2.380/B 511.1215 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.52 (d, J = 1.6 Hz, 1H) 9.29 (d, J = 1.6 Hz, 1H) 8.34-8.45 (m, 2H) 8.23(d, J = 7.8 Hz, 1H) 7.75 (d, J = 7.8 Hz, 1H) 7.65 (t, J = 7.6 Hz, 1H)7.01 (s, 1H) 6.84 (d, J = 0.8 Hz, 1H) 6.57 (d, J = 1.6 Hz, 1H) 5.38 (s,2H) 4.20 (s, 3H) 3.80 (s, 3H) 43

C₂₇H₁₉F₃N₄O₄S 553.1152 2.500/B 553.1183 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.07 (dd, J = 1.6, 0.8 Hz, 1H) 8.38 (s, 1H) 8.29-8.35 (m, 2H) 8.21-8.27(m, 1H) 8.14 (dt, J = 7.8, 1.6 Hz, 1H) 7.68 (dt, J = 7.5, 1.5 Hz, 1H)7.60 (t, J = 7.6 Hz, 1H) 7.01 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0, 0.8Hz, 1H) 6.57 (d, J = 2.0 Hz, 1H) 5.37 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H)44

C₂₆H₁₉FN₄O₄S 503.1184 2.371/B 503.1214 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.55-8.59 (m, 1H) 8.38 (s, 1H) 8.07 (d, J = 1.6 Hz, 1H) 7.82-7.92 (m,2H) 7.63 (dt, J = 7.7, 1.4 Hz, 1H) 7.58 (t, J = 7.6 Hz, 1H) 7.47-7.54(m, 1H) 6.98 (d, J = 0.8 Hz, 1H) 6.83 (dd, J = 2.0, 0.8 Hz, 1H) 6.57 (d,J = 2.0 Hz, 1H) 5.36 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 45

C₂₆H₁₉FN₄O₄S 503.1184 2.358/B 503.1258 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.24-8.28 (m, 1 H) 8.11- 8.19 (m, 1H) 7.77 (d, J = 1.2 Hz,1H) 7.54- 7.63 (m, 3H) 7.50 (ddd, J = 7.3, 5.0, 2.2 Hz, 1H) 6.99 (d, J =0.8 Hz, 1H) 6.84 (dd, J = 2.0, 0.8 Hz, 1H) 6.57 (d, J = 2.0 Hz, 1H) 5.33(s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 46

C₂₇H₁₉N₅O₄S 510.1231 2.288/ 510.1248 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.95 (s, 1H) 8.85 (d, J = 5.1 Hz, 1H) 8.37 (s, 1 H) 8.01 (d, J = 5.1 Hz,1H) 7.82-7.86 (m, 1H) 7.61-7.72 (m, 3H) 7.03 (s, 1H) 6.82-6.86 (m, 1H)6.59 (d, J = 1.6 Hz, 1H) 5.34 (s, 2 H) 4.20 (s, 3H) 3.81 (s, 3H) 47

C₂₆H₂₁N₅O₅S 516.1336 2.361/B 516.1367 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.96 (s, 2H) 8.37 (s, 1H) 7.88 (s, 1H) 7.69- 7.74 (m, 1H) 7.52-7.59 (m,2H) 7.02 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0, 0.8 Hz, 1H) 6.57 (d, J =1.6 Hz, 1H) 5.32 (s, 2H) 4.20 (s, 3H) 3.98 (s, 3H) 3.80 (s, 3H) 48

C₂₄H₁₈N₄O₄S₂ 491.0842 2.363/B 491.0867 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.40 (s, 1H) 9.08 (s, 1H) 8.38 (s, 1H) 7.95 (s, 1H) 7.76-7.82 (m, 1H)7.48-7.54 (m, 2H) 7.01 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 1.8, 1.0 Hz,1H) 6.57 (d, J = 2.0 Hz, 1H) 5.30 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 49

C₂₈H₂₅N₅O₄S 528.1700 2.094/B 528.1727 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.32 (s, 1H) 8.13 (br. s, 1H) 7.79 (s, 1H) 7.61-7.68 (m,1H) 7.51 (d, J = 5.5 Hz, 2H) 7.08 (br. s, 1H) 7.00 (d, J = 0.8 Hz, 1H)6.84 (dd, J = 2.0, 0.8 Hz, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.32 (s, 2H)4.20 (s, 3H) 3.80 (s, 3H) 3.17 (s, 6H) 50

C₂₆H₁₈ClFN₄O₄S 537.0794 2.534/B 537.0818 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.66 (dd, J = 2.2, 1.4 Hz, 1H) 8.38 (s, 1H) 8.23 (dd, J = 11.2, 2.2 Hz,1H) 8.05 (d, J = 1.2 Hz, 1H) 7.88 (dq, J = 7.7, 1.6 Hz, 1H) 7.65 (dt, J= 7.5, 1.5 Hz, 1H) 7.59 (t, J = 7.8 Hz, 1H) 6.98 (d, J = 0.8 Hz, 1H)6.83 (dd, J = 1.8, 1.0 Hz, 1H) 6.56 (d, J = 1.6 Hz, 1H) 5.36 (s, 2H)4.20 (s, 3H) 3.79 (s, 3H) 51

C₂₈H₂₄N₄O₅S 529.157 2.419/B 529.154 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.37(s, 1H) 7.99 (s, 1H) 7.46-7.55 (m, 3H) 7.33 (dt, J = 6.7, 1.9 Hz, 1H)6.97 (d, J = 0.8 Hz, 1H) 6.83 (dd, J = 1.8, 1.0 Hz, 1H) 6.78 (d, J = 0.8Hz, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.32 (s, 2H) 4.20 (s, 3H) 3.86 (s, 3H)3.79 (s, 3H) 2.20 (d, J = 0.8 Hz, 3 H) 52

C₂₇H₂₁ClN₄O₄S 533.1045 2.434/B 533.1073 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.52-8.55 (m, 1H) 8.37 (s, 1H) 7.90- 7.94 (m, 1H) 7.67 (s, 1H) 7.58 (qd,J = 4.2, 1.5 Hz, 1H) 7.50-7.54 (m, 2H) 6.97 (d, J = 0.8 Hz, 1H) 6.83(dd, J = 1.8, 1.0 Hz, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.33 (s, 2H) 4.20 (s,3H) 3.79 (s, 3H) 2.33 (s, 3H) 53

C₂₆H₂₁N₅O₅S 516.1336 2.449/BS 516.1359 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.83 (d, J = 1.6 Hz, 1H) 8.41 (d, J = 1.6 Hz, 1H) 8.38 (s, 1H) 8.16-8.19(m, 1H) 8.00 (dt, J = 7.1, 1.9 Hz, 1H) 7.51-7.60 (m, 2H) 7.00 (d, J =0.8 Hz, 1H) 6.83 (dd, J = 1.8, 1.0 Hz, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.34(s, 2H) 4.20 (s, 3H) 3.97 (s, 3H) 3.80 (s, 3H) 54

C₂₆H₁₈Cl₂N₄O₄S 553.0449 2.526/B 553.052 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.73 (d, J = 2.0 Hz, 1H) 8.35-8.39 (m, 2H) 7.82 (t, J = 1.6 Hz, 1H) 7.66(dt, J = 7.7, 1.6 Hz, 1H) 7.63 (dt, J = 7.8, 1.5 Hz, 1H) 7.55 (t, J =7.6 Hz, 1H) 6.98 (d, J = 0.8 Hz, 1H) 6.83 (dd, J = 1.8, 1.0 Hz, 1H) 6.56(d, J = 1.6 Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 55

C₂₆H₁₉FN₄O₄S 503.1184 2.375/B 503.121 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.33 (d, J = 5.1 Hz, 1H) 8.01 (t, J = 1.6 Hz, 1H) 7.85 (dt,J = 7.8, 1.6 Hz, 1H) 7.73 (dt, J = 5.2, 1.7 Hz, 1H) 7.63- 7.69 (m, 1H)7.54-7.63 (m, 2H) 7.01 (s, 1H) 6.82-6.86 (m, 1H) 6.57 (d, J = 2.0 Hz,1H) 5.34 (s, 2 H) 4.20 (s, 3H) 3.80 (s, 3H) 56

C₂₆H₁₉ClN₄O₄S 519.0888 2.415/B 519.0913 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.77 (dd, J = 2.7, 0.8 Hz, 1H) 8.37 (s, 1H) 8.19 (dd, J = 8.4, 2.5 Hz,1H) 7.89 (t, J = 1.8 Hz, 1H) 7.73 (dt, J = 7.2, 1.7 Hz, 1H) 7.52- 7.65(m, 3H) 7.01 (d, J = 0.8 Hz, 1H) 6.84 (dd, J = 2.0, 0.8 Hz, 1H) 6.57 (d,J = 2.0 Hz, 1H) 5.33 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3 H) 57

C₃₁H₂₇N₅O₆S 598.1775 2.267/B 598.1884 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.93 (dd, J = 2.3, 0.8 Hz, 1 H) 8.38 (s, 1 H) 8.25 (dd, J = 8.2, 2.3 Hz,1 H) 7.92 (t, J = 1.8 Hz, 1 H) 7.77 (dt, J = 7.1, 1.9 Hz, 1 H) 7.72 (dd,J = 8.2, 0.8 Hz, 1 H) 7.53- 7.64 (m, 2 H) 7.01 (d, J = 0.8 Hz, 1 H) 6.84(dd, J = 1.8, 1.0 Hz, 1 H) 6.57 (d, J = 2.0 Hz, 1H) 5.34 (s, 2H) 4.20(s, 3H) 3.80 (s, 3H) 3.68 (s, 4H) 3.48-3.61 (m, 4H) 58

C₂₇H₂₃N₅O₆S 546.1442 2.305/B 546.1478 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.38 (s, 1H) 8.33 (s, 1H) 8.22 (d, J = 0.8 Hz, 1H) 8.03 (s, 1 H)7.81-7.87 (m, 1H) 7.46-7.53 (m, 2H) 6.99 (s, 1H) 6.81- 6.85 (m, 1H) 6.55(d, J = 2.0 Hz, 1H) 5.30 (s, 2H) 5.30 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H)3.35 (s, 3H) 59

C₃₀H₂₇N₅O₅S 570.1806 570.1861 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (d, J= 2.3 Hz, 1H) 8.38 (s, 1H) 7.90 (dd, J = 8.8, 2.5 Hz, 1H) 7.73-7.78 (m,1H) 7.61 (dt, J = 7.2, 1.7 Hz, 1H) 7.41- 7.51 (m, 2H) 6.98-7.01 (m, 1H)6.94 (d, J = 9.0 Hz, 1H) 6.83 (dd, J = 1.8, 1.0 Hz, 1H) 6.56 (d, J = 2.0Hz, 1H) 5.30 (s, 2H) 4.20 (s, 3H) 3.79 (s, 3H) 3.68-3.75 (m, 4H)3.46-3.54 (m, 4H) 60

C₃₁H₂₈N₄O₆S 585.1802 2.510/B 585.1849 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.01-9.07 (m, 1H) 8.38 (s, 1H) 8.28 (dd, J = 8.2, 2.3 Hz, 1H) 8.05-8.10(m, 1H) 7.91-7.97 (m, 1H) 7.79 (dt, J = 7.2, 1.9 Hz, 1H) 7.56-7.66 (m,2H) 6.99-7.03 (m, 1H) 6.84 (dd, J = 1.8, 1.0 Hz, 1H) 6.58 (d, J = 1.6Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H) 1.58 (s, 9H) 61

C₃₆H₃₂N₄O₆S 649.2115 2.413/B 649.2145 ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.65 (d, J = 2.0 Hz, 1H) 8.38 (s, 1H) 8.25 (t, J = 2.0 Hz, 1H) 8.06 (dt,J = 7.7, 1.6 Hz, 1H) 8.00 (dd, J = 8.2, 0.8 Hz, 1 H) 7.87 (dd, J = 8.4,2.2 Hz, 1H) 7.51-7.61 (m, 2H) 7.21-7.26 (m, 2H) 7.00 (d, J = 0.8 Hz, 1H)6.87-6.92 (m, 2H) 6.83 (dd, J = 2.0, 0.8 Hz, 1H) 6.57 (d, J = 2.0 Hz,1H) 5.35 (s, 2H) 4.64 (q, J = 6.3 Hz, 1H) 4.32 (s, 2H) 4.20 (s, 3H) 3.79(s, 3H) 3.74 (s, 3H) 1.44 (d, J = 6.3 Hz, 3H)

Example 626-(4-((3-Fluoro-5-(5-methoxypyridin-2-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

62A. 3-Fluoro-5-(5-methoxypyridin-2-yl)benzoic acid

In a 4 mL vial, palladium acetate (4.9 mg, 0.022 mmol),triphenylphosphine (12.1 mg, 0.046 mmol), 2M aqueous solution of sodiumcarbonate (0.96 ml, 1.920 mmol) and water (0.3 ml, 16.65 mmol) weresuccessively added to a mixture of 2-bromo-5-methoxypyridine (0.1 ml,0.814 mmol) and 3-carboxy-5-fluorophenylboronic acid (148 mg, 0.805mmol) in 1-propanol (1.5 ml, 19.97 mmol) under nitrogen. The mixture wasstirred at 95° C. overnight. The mixture was quenched with 1N HCl andthe product was extracted three times with AcOEt. The aqueous phase wasneutralized to pH 7 with NaOH 10% and extracted twice with AcOEt. Thecombined organic layers were washed once with water, once with brine,dried over anh. Na₂SO₄ and concentrated. The white solid in suspensionin aqueous phase was filtrated and the two products were mixed togetherto give the title material as a white solid used as is. LC (Method B):1.747 min. ¹H NMR (400 MHz, acetone) δ ppm 8.54-8.58 (m, 1H) 8.41 (dd,J=3.1, 0.8 Hz, 1H) 8.07 (ddd, J=10.3, 2.7, 1.7 Hz, 1H) 8.03 (dd, J=9.0,0.8 Hz, 1H) 7.69 (ddd, J=9.0, 2.6, 1.4 Hz, 1H) 7.50 (dd, J=8.8, 2.9 Hz,1H) 3.96 (s, 3H).

62B. (3-Fluoro-5-(5-methoxypyridin-2-yl)phenyl)methanol

At 0° C. under nitrogen, lithium aluminum hydride (115 mg, 3.03 mmol)was added portionwise over 10 min. to3-fluoro-5-(5-methoxypyridin-2-yl)benzoic acid (Example 62A, 150 mg,0.607 mmol) in THF (6 ml, 73.2 mmol) and the mixture was stirred for 24h at room temperature. The reaction was quenched with water (1.5 mL) andstirred for 30 min. at room temperature. It was filtrated on CELITE®,washed with AcOEt and concentrated. The residue was purified on ISCOusing a REDISEP® Gold 24 g column (Hex/EtOAc). The crude product wasadsorbed on SiO₂. The fractions were collected and concentrated to givethe title material as a yellow oil (96 mgs, 96%). LC (Method B): 1.346min. MS(ESI) calcd for C₁₃H₁₃FNO₂ [M+H]⁺ m/z 234.0925. found 234.0962.¹H NMR (400 MHz, acetone) δ ppm 8.35-8.39 (m, 1H) 7.91 (dd, J=8.6, 0.8Hz, 1H) 7.85-7.89 (m, 1H) 7.63-7.70 (m, 1H) 7.45 (dd, J=8.6, 3.1 Hz, 1H)7.10-7.16 (m, 1H) 4.73 (d, J=5.9 Hz, 2H) 4.40 (t, J=5.9 Hz, 1H) 3.94 (s,3H).

Example 626-(4-((3-Fluoro-5-(5-methoxypyridin-2-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 51 mg, 0.161 mmol),(3-fluoro-5-(5-methoxypyridin-2-yl)phenyl)methanol (Example 62B, 96 mg,0.412 mmol) and triphenylphosphine (106 mg, 0.404 mmol) was dried underhigh vacuum for 10 min. THF (1.5 mL) was added and the mixture wassonificated for 15 min. Diisopropyl azodicarboxylate (0.08 ml, 0.411mmol) in THF (1.0 mL) was added portionwise over 15 min. and the yellowsolution was sonicated 30 min. and stirred 1 h 30 at room temperature.The mixture was diluted in CH₂Cl₂, washed once with sat. NaHCO₃, oncewith brine, dried over anh. Na₂SO₄ and concentrated. The residue waspurified on ISCO using a REDISEP® Gold 12 g column (CH₂Cl₂/EtOAc). Thecrude product was adsorbed on SiO₂. The fractions were concentrated,triturated once in ACN and lyophilized in ACN/water to give the titlematerial as a beige solid (58 mgs, 68%). LC (Method B): 2.376 min.MS(ESI) calcd for C₂₇H₂₂FN₄O₅S [M+H]⁺ m/z 533.1328. found 533.1318. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.40 (d, J=3.1 Hz, 1H) 8.39 (s, 1H) 8.04(t, J=1.6 Hz, 1H) 8.01 (d, J=8.6 Hz, 1H) 7.77-7.83 (m, 1H) 7.51 (dd,J=8.9, 3.0 Hz, 1H) 7.32-7.38 (m, 1H) 7.02-7.05 (m, 1H) 6.83-6.87 (m, 1H)6.55 (d, J=1.6 Hz, 1H) 5.35 (s, 2H) 4.21 (s, 3H) 3.89 (s, 3H) 3.80 (s,3H).

The following benzylic alcohols were prepared according to the proceduredescribed in Example 62A and 62B using 3-carboxy-5-fluorophenylboronicacid or (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid and thecorresponding bromides.

HPLC Calc. LCMS Retention Structure (Employed in preparation [M + H]⁺[M + H]⁺ Time (Min)/ of compound as indicated) Formula m/z m/z MethodNMR

  (70) C₁₂H₈F₃NO 240.06 240.0 1.760/B ¹H NMR (400 MHz, acetone): δ ppm8.56 (d, J = 2.7 Hz, 1H) 7.74-7.82 (m, 2H) 7.53-7.59 (m, 1H) 7.22-7.28(m, 1H) 4.76 (d, J = 5.9 Hz, 2H) 4.48 (t, J = 5.9 Hz, 1H)

Example 632-(1,1-Difluoroethyl)-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

63A. 5-(1,1-Difluoroethyl)-1,3,4-thiadiazol-2-amine

General Method: A modification of a literature procedure was used (cf.He, J. et al., Chinese Chemical Letters, 19:1281 (2008)). Thus, to anice-cold suspension of thiosemicarbazide (4.97 g, 54.5 mmol) in dioxane(45 mL) was slowly added a solution of the 2,2-difluoropropanoic acid(4.50 g, 40.9 mmol) in dioxane (5 mL). To the resulting thick off-whiteslurry was added POCl₃ (4.99 mL, 54.5 mmol) dropwise and then thecooling bath was removed and the mixture was stirred at room temperaturefor 1 h. The vessel was then sealed and the mixture was heated at 90-95°C. (oil bath temperature) for 5 h. The resulting turbid mixture wasconcentrated under reduced pressure and the concentrate was poured intoice water (150 mL). This mixture was basified to ca. pH 9 using 40%aqueous NaOH and the resulting slurry was filtered and the residue waswashed with water, then with ether and finally with hexanes. The residuewas dried in vacuo to give the title compound (4.31 g, 64%) as a whitesolid which was used as such in the next step. LC (Method A): 1.045 min.LCMS: Anal. Calcd. for C₄H₅F₂N₃S: 165.02. found: 166.04 (M+1)⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 7.69 (s, 2H), 2.06 (t, J=19.0 Hz, 3H).

63B.6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole

The reaction was split in two 20 mL vials.1-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1D,775 mg, 2.065 mmol) and 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine(Example 63A, 450 mg, 2.72 mmol) were suspended in 2-propanol (24 ml,312 mmol) and heated at 80° C. for 17 h. After 5 min., the solutionbecame homogeneous and a precipitate was present after stirringovernight. The cooled mixtures were then transferred into two 20 mLmicrowaves vials and then heated for 30 min at 150° C. The mixtures werecombined, diluted in CH₂Cl₂ (200 mL) and washed once with sat. NaHCO₃,once with brine, dried over anh. Na₂SO₄ and concentrated. The residuewas purified on ISCO using a REDISEP® Gold 24 g column (CH₂Cl₂/EtOAc).The orange solid obtained was triturated twice in MeOH to give the titlematerial (539 mg, 59%) as a light yellow solid. LC (Method B): 2.457min. MS(ESI) calcd for C₂₂H₁₈F₂N₃O₃S [M+H]⁺ m/z 442.1031. found442.1064. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.72 (s, 1H) 7.48-7.56 (m, 2H)7.42 (tt, J=7.4, 1.6 Hz, 2H) 7.35 (tt, J=7.4, 1.8 Hz, 1H) 7.12 (d, J=0.8Hz, 1H) 6.85 (dd, J=2.0, 0.8 Hz, 1H) 6.55 (d, J=2.0 Hz, 1H) 5.27 (s, 2H)3.80 (s, 3H) 2.24 (t, J=19.4 Hz, 3H).

63C.2-(2-(1,1-Difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol

A mixture of6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole(Example 63B, 0.534 g, 1.210 mmol) and pentamethylbenzene (1.264 g, 8.53mmol) in dichloromethane (80 ml, 1243 mmol) was cooled to −78° C. undernitrogen atmosphere and then treated immediately (to avoidcrystallization) with boron trichloride 1.0M in dichloromethane (3.2 ml,3.20 mmol) added dropwise over 3 min. The resulting mixture was stirredat −78° C. for 1 h. Boron trichloride (1.0M in DCM, 1.0 ml, 1.00 mmol)was added again and the mixture was stirred for an extra 1.5 hrs. Thereaction mixture was then quenched by addition of a solution of sodiumbicarbonate (2.4 g) in water (40 mL) added in one portion. The coolingbath was removed and the resulting mixture was stirred at roomtemperature for 1 h. The resulting solid was filtered, washedsuccessively with water (20 mL) and dichloromethane (20 mL). The filtercake was soaked with anh. ethanol and sucked dry. The white solidobtained was dried under vacuum on P₂O₅ over week-end to give the titlematerial (312 mg, 73%). LC (Method B): 2.134 min. MS(ESI) calcd forC₁₅H₁₂F₂N₃O₃S [M+H]⁺ m/z 352.0562. found 352.0579. ¹H NMR (400 MHz,DMSO-d₆) ppm 10.09 (s, 1H) 8.67 (s, 1H) 7.13 (s, 1H) 6.68 (dd, J=2.0,0.8 Hz, 1H) 6.27 (d, J=2.0 Hz, 1H) 3.76 (s, 3H) 2.24 (t, J=19.4 Hz, 3H).

Example 632-(1,1-Difluoroethyl)-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, benzene was added to2-(2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 63C, 26 mg, 0.074 mmol) and the mixture was sonificated 30 sec.and concentrated in vacuo to remove traces of water in the startingmaterial. Triphenylphosphine (49 mg, 0.187 mmol) and(3-(pyrimidin-5-yl)phenyl)methanol (43 mg, 0.231 mmol) were added andthe mixture was dried under high vacuum for 10 min. THF (1.2 mL) wasadded and the mixture was sonificated for 5 min.Diisopropylazodicarboxylate (0.035 ml, 0.180 mmol) in THF (0.8 mL) wasadded dropwise over 5 min. and the yellow solution was stirred overweekend at room temperature. The reaction mixture was diluted in CH₂Cl₂,washed once with sat. NaHCO₃, once with brine, dried over anh. Na₂SO₄and concentrated. The residue was purified on ISCO using a REDISEP® Gold12 g column (CH₂Cl₂/EtOAc). The crude product was adsorbed on SiO₂. Thefractions were collected, concentrated in vacuo and lyophilized inACN/water to give the title material as a white solid. LC (Method B):2.426 min. MS(ESI) calcd for C₂₆H₂₀F₂N₅O₃S [M+H]⁺ m/z 520.1249. found520.1248. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.21 (s, 1H) 9.18 (s, 2H) 8.71(s, 1H) 7.98 (s, 1H) 7.81 (d, J=7.0 Hz, 1H) 7.51-7.71 (m, 2H) 7.17 (s,1H) 6.80-6.93 (m, 1H) 6.60 (d, J=1.6 Hz, 1H) 5.35 (s, 2H) 3.81 (s, 3H)2.23 (t, J=19.4 Hz, 3H).

Example 64(S)-2-(1-Fluoroethyl)-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

64A. (S)-5-(1-Fluoroethyl)-1,3,4-thiadiazol-2-amine

A 350 mL sealable pressure vessel was charged with thiosemicarbazide(11.17 g, 122.5 mmol) and dry dioxane (100 mL), and the mixture wascooled at 0° C. under an N₂ atmosphere. To this rapidly stirring mixturewas slowly added a solution of (S)-2-fluoropropanoic acid (9.40 g, 102.1mmol, from Fritz-Langhals, E., Tetrahedron Asymmetry, 981 (1994)) indioxane (10 mL). To the resulting mixture was added POCl₃ (11.22 mL,122.5 mmol) dropwise, then the cooling bath was removed and the thickwhite slurry was stirred at room temperature for 1 h. The vessel wasthen sealed and the mixture was heated at 90-95° C. (oil bathtemperature) for 5 h. The cooled mixture was stirred at room temperaturefor 14 h (Note: this was for convenience only and is optional) and thenthe supernatant (two-phase mixture) was decanted and concentrated underreduced pressure. The lower phase was slowly poured into ice water (250mL) and then the concentrate was also added. This mixture was rapidlystirred until it was essentially a homogeneous (turbid) solution, andthen it was basified to pH 9-9.5 using 40% aqueous NaOH. The resultingslurry was filtered and the filter-cake was washed with water (Note: LCof this beige solid showed that it contained only a trace of the desiredproduct, so it was not further investigated). The combined filtrate wasthen extracted with EtOAc (×3) and the organic phase was dried (Na₂SO₄)and evaporated to give a cream solid (10.58 g, 70%) which was theessentially pure product according to LC and LCMS. This material wasused as such without further purification. An analytical sample waspurified by flash chromatography [Isco/0-20% (MeOH—NH₄OH, 9:1)-DCM] togive a white solid. LC (Method B): 0.608 min. MS(ESI) calcd. forC₄H₆FN₃S m/z: 147.03. found: 148.05 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ7.38 (s, 2H), 5.82 (dq, J=6.4, 48.0 Hz, 1H), 1.65 (dd, J=6.4, 24.0 Hz,3H). Chiral LC: S:R=95:5.

64B.(S)-6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole

In a 20 mL vial,1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1D,407 mg, 1.085 mmol) and (S)-5-(1-fluoroethyl)-1,3,4-thiadiazol-2-amine(202 mg, 1.373 mmol) were suspended in 2-propanol (10 ml, 130 mmol) andheated at 80° C. for 18 h. After 5 min. the solution became homogeneous.A precipitate was present after ON stirring. The cooled mixtures weretransferred into 20 mL microwaves vials and then heated 30 min at 150°C. The mixtures were combined, diluted in CH₂Cl₂ (200 mL) and washedonce with sat. NaHCO₃, once with brine, dried over anh. Na₂SO₄ andconcentrated. The residue was purified on ISCO using a REDISEP® Gold 40g column (CH₂Cl₂/EtOAc). The crude product was adsorbed on SiO₂.Fractions were collected and the orange solid obtained was trituratedtwice in ACN to give the title material a light yellow solid. LC (MethodB): 2.403 min. MS(ESI) calcd. for C₂₂H₁₉FN₃O₃S [M+H]⁺ m/z: 424.1126.found: 424.1146. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (s, 1H) 7.51 (d,J=7.4 Hz, 2H) 7.42 (t, J=7.6 Hz, 2H) 7.35 (t, J=7.0 Hz, 1H) 7.08 (s, 1H)6.83-6.85 (m, 1H) 6.54 (d, J=1.2 Hz, 1H) 6.16 (dq, J=47.1, 6.4 Hz, 1H)5.26 (s, 2H) 3.80 (s, 3H) 1.79 (dd, J=24.5, 6.8 Hz, 3H).

64C.(S)-2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol

A mixture of(S)-6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole(Example 64B, 0.152 g, 0.359 mmol) and pentamethylbenzene (0.374 g, 2.52mmol) in dichloromethane (24 ml, 373 mmol) was cooled to −78° C. undernitrogen atmosphere and then treated immediately (to avoidcrystallization) with boron trichloride 1.0M in dichloromethane (1 ml,1.000 mmol) added dropwise over 3 min. The resulting mixture was stirredat −78° C. for 1 h. The reaction mixture was quenched by addition of asolution of sodium bicarbonate (0.71 g) in water (12 mL) added in oneportion. The cooling bath was removed and the resulting mixture wasstirred at room temperature for 1 h. The solid formed was filtered,washed successively with water (8 mL) and dichloromethane (8 mL). Thefilter cake was soaked with anh. ethanol and suck dried. The white solidobtained was dried under vacuum on P₂O₅ for 36 h. LC (Method B): 2.038min. MS(ESI) calcd. for C₁₅H₁₃FN₃O₃S [M+H]⁺ m/z: 334.0656. found:334.0680. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.06 (s, 1H) 8.56 (s, 1H)7.09 (s, 1H) 6.67 (s, 1H) 6.26-6.28 (m, 1H) 6.16 (dq, J=46.9, 6.4 Hz,1H) 3.76 (s, 3H) 1.80 (dd, J=24.7, 6.3 Hz, 3H).

Example 64(S)-2-(1-Fluoroethyl)-6-(6-methoxy-4-((3-(pyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, benzene was added to(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 64C, 17 mg, 0.051 mmol) and the mixture was sonificated during30 sec. and concentrated in vacuo to remove traces of water in thestarting material. Triphenylphosphine (30 mg, 0.114 mmol) and(3-(pyrimidin-5-yl)phenyl)methanol (33 mg, 0.177 mmol) were added andthe mixture was dried on high vacuum for 10 min. THF (1.0 mL) was addedand the mixture was stirred until complete dissolution.Diisopropylazodicarboxylate (0.025 ml, 0.129 mmol) in THF (0.5 mL) wasadded dropwise on 5 min. and the yellow solution was stirred overnightat room temperature. The reaction mixture was diluted in CH₂Cl₂, washedonce with sat. NaHCO₃, once with brine, dried over anh. Na₂SO₄ andconcentrated. The residue was purified on ISCO using a REDISEP® Gold 12g column (CH₂Cl₂/EtOAc). The crude product was adsorbed on SiO₂ and thefractions were collected, concentrated in vacuo, triturated once withACN and lyophilized in ACN/water to give the title material as a lightyellow solid. LC (Method B): 2.331 min. MS(ESI) calcd. for C₂₆H₂₁FN₅O₃S[M+H]⁺ m/z: 502.1344. found: 502.1353.

Example 656-(4-((5-(Furan-3-yl)pyridin-3-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

65A. (5-Bromopyridin-3-yl)methanol

To a cold solution of ethyl 5-bromonicotinate (1.003 g, 4.36 mmol) inmethanol (15 ml, 371 mmol) was added sodium borohydride (0.652 g, 17.23mmol) portionwise on 10 min. The reaction was stirred for 30 min. at 0°C. The reaction was quenched with water and extracted three times withCH₂Cl₂. The combined organic layers were dried on anh. Na₂SO₄ andconcentrated. The residue was purified on ISCO using a 80 g SILICYCLE®column (Hex/EtOAc) and afforded the title material (0.477 g, 54%) as aclear oil. LC (Method B): 0.756 min. MS(ESI) calcd. for C₆H₇BrNO [M+H]⁺m/z: 187.97. found: 190.0, 191.0. ¹H NMR (400 MHz, acetone) δ ppm8.50-8.58 (m, 2H) 7.93-7.98 (m, 1H) 4.67-4.74 (m, 2H) 4.48-4.56 (m, 1H).

65B. (5-(Furan-3-yl)pyridin-3-yl)methanol

In a 2 mL vial, palladium acetate (5.5 mg, 0.024 mmol),triphenylphosphine (13.2 mg, 0.050 mmol), 2M aqueous solution of sodiumcarbonate (0.63 ml, 1.260 mmol) and water (0.35 ml, 19.43 mmol) weresuccessively added to a mixture of furan-3-ylboronic acid (Example 65A,112 mg, 1.001 mmol) and (5-bromopyridin-3-yl)methanol (170 mg, 0.904mmol) in 1-propanol (1.75 ml, 23.30 mmol) under nitrogen. The mixturewas stirred at 95° C. for 30 min. and the reaction was stirred at roomtemperature overnight. The mixture was quenched with water and theproduct was extracted three times with AcOEt. The combined organiclayers were washed once with sat. NaHCO₃, once with brine, dried overanh. Na₂SO₄ and concentrated. The residue was purified on silica gelusing a REDISEP® Gold 24 g column (Hex/EtOAc). The title material wasobtained (149 mgs, 94%) after concentration of the fractions as a lightyellow oil. LC (Method B): 0.702 min. MS(ESI) calcd. for C₁₀H₁₀NO₂[M+H]⁺ m/z: 176.07. found: 176.2. ¹H NMR (400 MHz, acetone) δ ppm 8.73(d, J=2.0 Hz, 1H) 8.46 (d, J=2.0 Hz, 1H) 8.11-8.17 (m, 1H) 7.90-7.95 (m,1H) 7.67-7.72 (m, 1H) 6.97 (dd, J=2.0, 0.8 Hz, 1H) 4.71 (d, J=6.3 Hz,2H) 4.38 (t, J=5.7 Hz, 1H).

Example 656-(4-((5-(Furan-3-yl)pyridin-3-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

In a 10 mL round-bottomed flask, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 45 mg, 0.142 mmol) and triphenylphosphine (100 mg, 0.381mmol) was dried on high vacuum for 10 min. THF (1.0 mL) was added andthe mixture was sonificated for 10 min. A mixture of(5-(furan-3-yl)pyridin-3-yl)methanol (Example 65B, 61 mg, 0.348 mmol)and diisopropyl azodicarboxylate (0.08 ml, 0.411 mmol) in THF (1.5 mL)was added portionwise on 10 min. and the yellow solution was sonicatedfor 20 min. and stirred for 2 h at room temperature. The mixture wasdiluted in CH₂Cl₂, washed once with sat. NaHCO₃, once with brine, driedover anh. Na₂SO₄ and concentrated. The residue was purified on ISCOusing a REDISEP® Gold 12 g column (CH₂Cl₂/EtOAc). The fractions wereconcentrated, triturated twice in ACN to give an impure beige solid. Theresidue was purified for a second time on ISCO using a REDISEP® Gold 12g column (CH₂Cl₂/EtOAc). The fractions were concentrated, triturated inACN and lyophilized in ACN/water to give the title material (12 mgs,18%) as a white solid. LC (Method B): 2.096 min. MS(ESI) calcd. forC₂₄H₁₉N₄O₅S [M+H]⁺ m/z: 475.1071. found: 475.1224. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 8.88 (d, J=2.3 Hz, 1H) 8.61 (d, J=2.0 Hz, 1H) 8.38 (s,1H) 8.36-8.37 (m, 1H) 8.16 (t, J=2.2 Hz, 1H) 7.82 (t, J=1.8 Hz, 1H) 7.10(dd, J=2.0, 0.8 Hz, 1H) 7.02 (d, J=0.8 Hz, 1H) 6.86 (dd, J=1.8, 1.0 Hz,1H) 6.60 (d, J=2.0 Hz, 1H) 5.32 (s, 2H) 4.20 (s, 3H) 3.81 (s, 3H).

The following benzylic alcohols were prepared according to the proceduredescribed in Example 65A and 65B using (5-bromopyridin-3-yl)methanol andthe corresponding boronic acids and were employed in preparationcompounds of the Examples as indicated.

HPLC Retention Calc. LCMS Time Structure (Employed in preparation [M +H]⁺ [M + H]⁺ (Min)/ of Example compound as indicated) Formula m/z m/zMethod NMR

  (72) C₁₂H₁₁NO 186.09 186.2 0.990/B ¹H NMR (400 MHz, acetone) δ ppm8.75 (d, J = 2.3 Hz, 1H) 8.56 (d, J = 2.3 Hz, 1H) 7.96-8.02 (m, 1H)7.68-7.74 (m, 2H) 7.47-7.55 (m, 2H) 7.39-7.46 (m, 1H) 4.76 (d, J = 5.9Hz, 2H) 4.42 (t, J = 5.9 Hz, 1H)

  (73) C₁₃H₁₄NO₂ 216.10 216.2 1.101/B ¹H NMR (400 MHz, acetone) δ ppm8.71 (d, J = 2.3 Hz, 1H) 8.50 (d, J = 2.0 Hz, 1H) 7.92-7.96 (m, 1H)7.61-7.68 (m, 2H) 7.04-7.10 (m, 2H) 4.74 (d, J = 6.3 Hz, 2H) 4.39 (t, J= 5.7 Hz, 1H) 3.86 (s, 3H)

  (74) C₁₁H₉ClN₂O 221.05 221.0 0.910/B ¹H NMR (400 MHz, acetone) δ ppm8.81 (d, J = 2.3 Hz, 1H) 8.72-8.78 (m, 1H) 8.64 (d, J = 2.0 Hz, 1H) 8.18(dd, J = 8.2, 2.4 Hz, 1H) 8.05-8.09 (m, 1H) 7.60 (dd, J =8.2, 0.8 Hz,1H) 4.75- 4.80 (m, 2H) 4.48 (t, J = 5.7 Hz, 1H)

  (75) C₁₁H₁₁N₃O₂ 218.09 218.2 0.752/B ¹H NMR (400 MHz, acetone) δ ppm8.91 (s, H) 8.79 (d, J = 2.3 Hz, 1H) 8.60-8.64 (m, 1H) 8.02-8.07 (m, 1H)4.75-4.79 (m, 2H) 4.47 (t, J = 5.9 Hz, 1H) 4.02 (s, 3H)

  (76) C₁₁H₉ClN₂O 221.05 221.0 1.455/B ¹H NMR (400 MHz, acetone) δ ppm9.11 (dd, J = 2.3, 0.8 Hz, 1H) 8.53 (dd, J = 8.4, 2.5 Hz, 1H) 7.87-7.98(m, 2H) 7.50- 7.61 (m, 2H) 4.78 (d, J = 5.9 Hz, 2H) 4.53 (t, J = 5.9 Hz,1H)

  (77) C₁₁H₁₁N₃O₂ 218.09 218.2 1.243/B ¹H NMR (400 MHz, acetone) δ ppm9.24 (s, 2H) 7.91 (t, J = 7.6 Hz, 1H) 7.82-7.87 (m, 1H) 7.48-7.54 (m,1H) 4.77 (d, J = 5.9 Hz, 2H) 4.52 (t, J = 5.7 Hz, 1H) 4.02 (s, 3H)

  (78) C₁₃H₁₃NO₂ 216.10 216.2 1.214/B ¹H NMR (400 MHz, acetone) δ ppm8.06-8.12 (m, 2H) 7.81 (t, J = 7.6 Hz, 1H) 7.69-7.76 (m, 1H) 7.33-7.40(m, 1H) 6.99- 7.06 (m, 2H) 4.74 (d, J = 5.9 Hz, 2H) 4.46 (t, J = 5.5 Hz,1H) 3.86 (s, 3H)

Example 666-(4-((3-(6-Chloropyridin-3-yl)-5-methoxybenzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1b][1,3,4]thiadiazole

66A. (3-Bromo-5-methoxyphenyl)methanol

Boron methyl sulfide complex (1.4 ml, 14.00 mmol) was added dropwise toa solution of 3-bromo-5-methoxybenzoic acid (0.866 g, 3.75 mmol) in THF(20 ml, 244 mmol) under nitrogen at room temperature. The resultingmixture was stirred at 65° C. for 5 h. At 0° C., water was addeddropwise and the reaction mixture was concentrated in vacuo. The residuewas diluted in AcOEt and washed successively with 1N NaOH, 1N HCl, sat.NaHCO₃ and brine, dried over anh. Na₂SO₄ and concentrated. The residuewas purified on ISCO using a REDISEP® Gold 24 g column (Hex/EtOAc). Thetitle material (0.746 g, 92%) was obtained as a white solid afterconcentration of the fractions. LC (Method B): 1.749 min. ¹H NMR (400MHz, acetone) δ ppm 7.11 (dq, J=2.1, 0.9 Hz, 1H) 6.97 (t, J=2.2 Hz, 1H)6.93 (dq, J=2.3, 1.1 Hz, 1H) 4.57-4.63 (m, 2H) 4.33 (t, J=5.9 Hz, 1H)3.81 (s, 3H).

66B. (3-(6-Chloropyridin-3-yl)-5-methoxyphenyl)methanol

In a 4 mL vial, palladium(II) acetate (0.0051 g, 0.023 mmol),triphenylphosphine (0.012 g, 0.046 mmol), 2M sodium carbonate (0.62 ml,1.240 mmol) and water (0.3 ml, 16.65 mmol) were successively added to amixture of (3-bromo-5-methoxyphenyl)methanol (Example 66A, 0.191 g,0.880 mmol) and 6-chloropyridin-3-yl)boronic acid (0.151 g, 0.960 mmol)in 1-propanol (1.5 ml, 19.97 mmol) under nitrogen. The mixture wasstirred at 85° C. for 30 min. and was quenched with water. The productwas extracted three times with AcOEt and the combined organic layerswere washed once with sat. NaHCO₃, once with brine, dried over anh.Na₂SO₄ and concentrated. The residue was purified on ISCO using a 40 gSILICYCLE® column (Hex/EtOAc) to afford the desired compound (0.055 g,25%) as a colorless oil. LC (Method B): 1.797 min. MS(ESI) calcd. forC₁₃H₁₃ClNO₂ [M+H]⁺ m/z: 250.06. found: 250.0. ¹H NMR (400 MHz, acetone)δ ppm 8.68 (dd, J=2.7, 0.8 Hz, 1H) 8.10 (dd, J=8.2, 2.7 Hz, 1H) 7.53(dd, J=8.2, 0.8 Hz, 1H) 7.24-7.28 (m, 1H) 7.13 (t, J=2.0 Hz, 1H) 7.04(dd, J=2.2, 1.0 Hz, 1H) 4.70 (d, J=5.9 Hz, 2H) 4.29 (t, J=5.9 Hz, 1H)3.88 (s, 3H).

Example 666-(4-((3-(6-Chloropyridin-3-yl)-5-methoxybenzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1b][1,3,4]thiadiazole

In a 20 mL vial, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.044 g, 0.139 mmol) and(3-(6-chloropyridin-3-yl)-5-methoxyphenyl)methanol (Example 66A, 0.055g, 0.220 mmol) was dried 5 min. on high vacuum. Tri-n-butylphosphine(0.085 ml, 0.345 mmol) and THF (3 mL) were added and the mixture wassonificated for 10 min under nitrogen. A solution of1,1′-(azodicarbonyl)dipiperidine (0.088 g, 0.349 mmol) in THF (1.5 mL)was added dropwise for 10 min. and the heterogeneous mixture was stirredfor 3 h at room temperature. The mixture was diluted in CH₂Cl₂, washedonce with sat. NaHCO₃, once with brine, dried over anh. Na₂SO₄ andconcentrated. The residue was purified on ISCO using a REDISEP® Gold 24g column (CH₂Cl₂/EtOAc). The fractions were combined and concentrated togive a residue which was purified again on ISCO using a REDISEP® Gold 24g column (CH₂Cl₂/EtOAc). The desired product (0.056 g, 74%) was obtainedas an off-white solid after concentration of the fractions andlyophilization in CAN/water. LC (Method B): 2.518 min. MS(ESI) calcd.for C₂₇H₂₂ClN₄O₅S [M+H]⁺ m/z: 549.0994. found: 549.1006 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.74-8.79 (m, 1H) 8.38 (s, 1H) 8.20 (dd, J=8.6, 2.7 Hz,1H) 7.62 (d, J=7.8 Hz, 1H) 7.45 (t, J=1.4 Hz, 1H) 7.27 (t, J=2.0 Hz, 1H)7.13-7.18 (m, 1H) 6.99-7.03 (m, 1H) 6.81-6.86 (m, 1H) 6.56 (d, J=1.6 Hz,1H) 5.29 (s, 2H) 4.20 (s, 3H) 3.86 (s, 3H) 3.80 (s, 3H).

The following benzylic alcohol was prepared according to the proceduredescribed in Example 66A and 66B using (3-bromo-5-methoxyphenyl)methanoland the corresponding boronic acid and used in preparing the compound ofExample 71.

HPLC Calc. LCMS Retention [M + H]⁺ [M + H]⁺ Time (Min)/ StructureFormula m/z m/z Method NMR

C₁₃H₁₄N₂O₃ 247.11 247.2 1.637/B ¹H NMR (400 MHz, acetone) δ ppm 8.83 (s,2H) 7.23 (s, 1H) 7.11 (t, J = 2.2 Hz, 1H) 7.00- 7.05 (m, 1H) 4.69 (d, J= 6.3 Hz, 2H) 4.28 (t, J = 5.9 Hz, 1H) 4.00 (s, 3 H) 3.88 (s, 3H)

Examples 67 to 80

The following additional Examples have been prepared, isolated andcharacterized using the method disclosed above.

HPLC Calc. Retention LCMS [M + H]⁺ Time (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 67

C₂₇H₁₉F₃N₄O₃S 537.1203 2.478/B 537.1111 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.72 (s, 1H) 8.68 (d, J = 2.7 Hz, 1H) 8.21 (s, 1H) 8.09 (dd, J = 8.8,3.7 Hz, 1H) 8.03 (dd, J = 7.8, 1.2 Hz, 1H) 7.85 (td, J = 8.7, 2.9 Hz,1H) 7.47-7.65 (m, 2H) 7.14 (s, 1H) 6.86 (s, 1H) 6.59 (s, 1H) 5.36 (s,2H) 3.81 (s, 3H) 2.24 (t, J = 19.2 Hz, 3H) 68

C₂₇H₁₉F₃N₄O₃S 537.1203 2.465/B 537.1065 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.71 (s, 1H) 8.58 (d, J = 2.7 Hz, 1H) 8.32 (td, J = 8.2, 2.7 Hz, 1H)7.87 (s, 1H) 7.71 (dt, J = 7.0, 2.0 Hz, 1H) 7.47-7.65 (m, 2H) 7.31 (dd,J = 8.6, 2.7 Hz, 1H) 7.15 (s, 1H) 6.87 (d, J = 0.8 Hz, 1H) 6.59 (d, J =l.6 Hz, 1H) 5.34 (s, 2H) 3.81 (s, 3H) 2.23 (t, J = 19.4 Hz, 3 H) 69

C₂₇H₂₀F₂N₄O₃S 519.1297 2.430/B 519.1308 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.67 (d, J = 3.1 Hz, 1H) 8.61 (s, 1H) 8.21 (s, 1H) 8.08 (dd, J = 8.8,4.5 Hz, 1H) 8.02 (d, J = 7.4 Hz, 1H) 7.85 (td, J = 8.7, 2.9 Hz, 1H)7.51- 7.63 (m, 2H) 7.10 (s, 1H) 6.80-6.90 (m, 1H) 6.58 (d, J = 1.6 Hz,1H) 6.17 (dq, J = 46.7, 6.5 Hz, 1H) 5.35 (s, 2H) 3.80 (s, 3H) 1.79 (dd,J = 24.6, 6.3 Hz, 3H) 70

C₂₆H₁₇F₃N₄O₄S 539.0995 2.481/B 539.1022 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.67 (d, J = 2.3 Hz, 1H) 8.38 (s, 1H) 8.13 (ddd, J = 11.3, 9.0, 2.3 Hz,1H) 7.87-7.91 (m, 1H) 7.61-7.68 (m, 1H) 7.46-7.53 (m, 1H) 7.02 (d, J =0.8 Hz, 1H) 6.85 (dd, J = 1.8, 1.0 Hz, 1H) 6.55 (d, J = 2.0 Hz, 1H) 5.38(s, 2H) 4.21 (s, 3H) 3.80 (s, 3H) 71

C₂₇H₂₃N₅O₆S 546.1442 2.439/B 546.1461 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.97 (s, 2H) 8.38 (s, 1H) 7.42-7.47 (m, 1H) 7.27 (t, J = 2.0 Hz, 1H)7.10-7.15 (m, 1H) 7.02 (s, 1H) 6.84 (dd, J = l.8, 0.6 Hz, 1H) 6.56 (d, J= 2.0 Hz, 1H) 5.28 (s, 2H) 4.20 (s, 3H) 3.97 (s, 3H) 3.85 (s, 3H) 3.80(s, 3H) 72

C₂₆H₂₀N₄O₄S 485.1278 2.205/B 485.1312 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.89 (d, J = 2.3 Hz, 1H) 8.73 (d, J = 2.3 Hz, 1H) 8.38 (s, 1H) 8.21 (t,J = 2.2 Hz, 1H) 7.74- 7.80 (m, 2H) 7.49-7.57 (m, 2H) 7.40-7.49 (m, 1H)7.02 (d, J = 0.8 Hz, 1H) 6.86 (dd, J = 2.0, 0.8 Hz, 1H) 6.61 (d, J = 2.0Hz, 1H) 5.38 (s, 2H) 4.20 (s, 3H) 3.81 (s, 3H) 73

C₂₇H₂₂N₄O₅S 515.1384 2.185/B 515.1422 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.84 (d, J = 2.0 Hz, 1H) 8.66 (d, J = 2.0 Hz, 1H) 8.38 (s, 1H) 8.15 (t,J = 2.2 Hz, 1H) 7.67-7.75 (m, 2H) 7.04-7.11 (m, 2H) 7.01 (d, J = 0.8 Hz,1H) 6.85 (dd, J = 2.0, 0.8 Hz, 1H) 6.61 (d, J = 2.0 Hz, 1H) 5.36 (s, 2H)4.20 (s, 3H) 3.81 (s, 3H) 3.81 (s, 3H) 74

C₂₅H₁₈ClN₅O₄S 520.0841 2.212/B 520.0884 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.96 (d, J = 2.3 Hz, 1H) 8.83-8.87 (m, 1H) 8.80 (d, J = 2.0 Hz, 1H) 8.37(s, 1H) 8.33 (t, J = 2.2 Hz, 1H) 8.29 (dd, J = 8.4, 2.5 Hz, 1H) 7.65-7.71 (m, 1H) 7.04 (d, J = 0.8 Hz, 1H) 6.86 (dd, J = 1.8, 1.0 Hz, 1H)6.62 (d, J = 2.0 Hz, 1H) 5.38 (s, 2H) 4.20 (s, 3H) 3.81 (s, 3H) 75

C₂₅H₂₀N₆O₅S 517.1289 2.132/B 517.1333 ¹H NMR (400 MHz, DMSO- d₆) δ ppm9.05 (s, 2H) 8.95 (d, J = 2.3 Hz, 1H) 8.77 (d, J = 2.0 Hz, 1H) 8.37 (s,1H) 8.32 (t, J = 2.2 Hz, 1H) 7.05 (d, J = 0.8 Hz, 1H) 6.86 (dd, J = 1.8,1.0 Hz, 1H) 6.62 (d, J = 2.0 Hz, 1H) 5.36 (s, 2H) 4.20 (s, 3H) 3.99 (s,3H) 3.81 (s, 3H) 76

C₂₅H₁₈ClN₅O₄S 520.0841 2.439/B 520.0871 ¹H NMR (400 MHz, DMSO- d₆) δ ppm9.10- 9.16 (m, 1H) 8.54 (dd, J = 8.4, 2.5 Hz, 1H) 8.39 (s, 1H) 7.97-8.10(m, 2H) 7.63-7.71 (m, 2H) 7.07 (d, J = 0.8 Hz, 1H) 6.85 (dd, J = 1.8,1.0 Hz, 1H) 6.57 (d, J = 2.0 Hz, 1H) 5.42 (s, 2H) 4.21 (s, 3H) 3.79 (s,3H) 77

C₂₅H₂₀N₆O₅S 517.1289 2.383/B 517.1389 ¹H NMR (400 MHz, DMSO- d₆) δ ppm9.27 (s, 2H) 8.39 (s, 1H) 7.94-8.05 (m, 2H) 7.62 (dd, J = 5.7, 2.9 Hz,1H) 7.07 (d, J = 0.8 Hz, 1H) 6.85 (dd, J = 1.8, 1.0 Hz, 1H) 6.57 (d, J =2.0 Hz, 1H) 5.41 (s, 2H) 4.21 (s, 3H) 4.00 (s, 3H) 3.79 (s, 3H) 78

C₂₇H₂₂N₄O₅S 515.1384 2.413/B 515.1427 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.39 (s, 1H) 8.04- 8.12 (m, 2H) 7.82-7.94 (m, 2H) 7.49 (dd, J = 7.2, 1.4Hz, 1H) 7.02-7.09 (m, 3H) 6.84 (dd, J = 1.6, 0.8 Hz, 1H) 6.57 (d, J =2.0 Hz, 1H) 5.38 (s, 2H) 4.21 (s, 3H) 3.82 (s, 3H) 3.78 (s, 3H) 80

C₂₅H₁₈N₄O₂S₂ 471.0944 2.453/A 471.0954 ¹H NMR (600 MHz, DMSO- d₆) δ ppm9.02 (s, 1H), 7.69 (dd, J₁ = 1.8 Hz, J₂ = 7.0 Hz, 1H), 7.51-7.46 (m,4H), 7.39 (t, J = 7.6 Hz, 3H), 7.36-7.33 (m, 2H), 7.26 (t, J = 8.2 Hz,1H), 6.85 (d, J = 8.2 Hz, 1H), 5.19 (s, 2H), 2.81 (s, 3H)

Example 814-((3-(Furan-3-yl)benzyl)oxy)-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazole

81A. Ethyl 2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate

A mixture of 2-amino-5-methylthio-1,3,4-thiadiazole (25 g, 0.17 mol),ethyl 3-bromopyruvate (23.7 mL, 0.189 mol) and ethanol (125 mL) in a 350mL sealable vessel was heated at 150° C. (oil bath temperature) for 20min. The cooled mixture was concentrated to dryness and the residue waspartitioned with ethyl acetate-saturated NaHCO₃. The organic phase waswashed (brine), dried (MgSO₄), filtered and concentrated to dryness. Theresidue was taken up in a minimum volume of dichloromethane and theresulting slurry was filtered and the filter-cake was washed with alittle dichloromethane. The solid was dried in vacuo to give recoveredamino-5-methylthio-1,3,4-thiadiazole (3.72 g, 15%). The filtrate wasconcentrated to dryness and the residue was crystallized from a minimumvolume of hot ethanol to give the title compound as a beige crystallinesolid (10.8 g, 0.044 mol, 26%). LC (Method E): 1.267 min. ¹H NMR (600MHz, DMSO-d₆) δ ppm 8.76 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.78 (s, 3H),1.28 (t, J=7.2 Hz, 3H).

81B. 2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid

To a stirred solution of ethyl2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylate (Example81A, 0.106 g, 0.434 mmol) in THF (4 mL) was added NaOTMS (0.608 mL,0.608 mmol). The reaction mixture was stirred at rt for 18 hours thenacidified to pH=3 with AcOH. The reaction mixture was concentrated todryness and triturated with H₂O (sonicated for 1 minute). The resultinglight yellow precipitate was filtered off and washed with Et₂O to affordthe title material (58 mg, 0.27 mmol, 62%). LC (Method E): 0.912 min;LCMS: Anal. Calcd. for C₆H₅N₃O₂S₂: 214.98. found: 215.99 (M+1)⁺. ¹H NMR(600 MHz, DMSO-d₆) δ ppm 12.69 (b.s, 1H), 8.66 (s, 1H), 2.79 (s, 3H).

81C. 2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carbonyl chloride

To a stirred suspension of2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid(Example 81B, 15 g, 0.070 mol) in DCM (350 mL) was added oxalyl chloride(29.5 mL, 0.348 mol) followed by DMF (1 drop). Gas evolution wasobserved and the reaction mixture stirred at ambient temperature for 3.5hours. The suspension was then concentrated to dryness to give alight-yellow solid and used as such by assuming a quantitative yield. LC(Method D): 1.686 min; ¹H NMR (600 MHz, DMSO-d₆) δ ppm 8.68 (s, 1H) 2.78(s, 3H).

81D.N-(2,6-Dihydroxyphenyl)-2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxamide

To a stirred suspension of 2-amino-1,3-benzenediol (4.28 g, 34.2 mmol)and 2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carbonyl chloride(Example 81C, 8 g, 34.2 mmol) in DMF (160 mL) was added triethylamine(9.53 mL, 68.4 mmol) at 0° C. The ice bath was allowed to dischargewhile the reaction mixture continued to stir overnight. The reactionmixture was then concentrated to dryness and triturated with methanol toafford the title material (4.61 g, 14.3 mmol, 42%). LC (Method D): 1.949min. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.89 (s, 1H), 8.91 (s, 1H), 8.75(s, 1H), 8.57 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H),6.77 (d, J=8.2 Hz, 1H), 2.75 (s, 3H).

81 E.2-(2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol

N-(2,6-Dihydroxyphenyl)-2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazole-6-carboxamide(Example 81D, 3×1.5 g, 13.95 mmol) was placed in a microwavable vialwith TFA (5 mL) and acetic acid (5 mL). The reaction was heated at 200°C. for 10 minutes. All 3 reaction mixtures were combined andconcentrated to near dryness. The residue was triturated with methanoland the solid material was filtered off. The solid was then dissolved inhot DMF and the insoluble material was filtered off. The filtrate wasconcentrated to dryness and triturated with water and saturated sodiumbicarbonate. The resulting solid was filtered off and dried underreduced pressure to give the title material as an off-white solid (1.28g, 4.19 mmol, 30%). LC (Method D): 1.937. MS(ESI) calcd. for C₁₂H₉N₄O₂S₂[M+H]⁺ m/z: 305.01. found: 305.04. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 10.39(s, 1H), 9.95 (s, 1H), 7.20-7.14 (m, 2H), 6.76 (dd, J₁=0.6 Hz, J₂=7.8Hz, 1H), 2.81 (s, 3H).

81F.2-(2-(Methylsulfonyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol

To a stirred solution of2-(2-(methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol(Example 81E, 610 mg, 2.004 mmol) in TFA (10 ml, 130 mmol) was addedtrifluoroperacetic acid (1.002 ml, 4.01 mmol). The resulting brownsolution was stirred at r.t. for 3 hours then stored in freezerovernight (˜16 hours). Trifluoroperacetic acid (0.5 ml) was added againand the mixture continued to stir for 2 hours then concentrated todryness. The mixture was triturated with MeOH and filtered off toprovide the title material as a brownish solid (600 mg, 1.784 mmol, 89%yield) which was used as such for the next reaction.

81G.2-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol

To a stirred solution of2-(2-(methylsulfonyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol(Example 81F, 600 mg, 1.784 mmol) in methanol (10 ml, 247 mmol) wasadded sodium methoxide (385 mg, 1.784 mmol). The resulting brownsolution was stirred at r.t. for 1 hour after which it was deemedincomplete by HPLC. Sodium methoxide (385 mg, 1.784 mmol) was addedagain and the reaction was stirred for 1 more hour. The reaction wasthen quenched with sat. NH₄Cl and the insoluble material was filteredoff. The insoluble material was suspended in DCM and adsorbed ontosilica gel. The residue was purified on ISCO using a REDISEP® Gold 24 gcolumn (CH₂Cl₂/EtOAc) to give the desired product as a light pink solid(136 mg, 0.472 mmol, 26.4% yield). The column was then flushed with 10%9:1 MeOH:NH₄OH in DCM which forced more compound to come off the column.Those fractions were concentrated to yield the desired product as a tansolid (85 mg, 0.295 mmol, 16.53% yield). LC (Method B): 1.816. MS(ESI)calcd. for C₁₂H₉N₄O₃S [M+H]⁺ m/z: 289.039. found: 289.0384. ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.36 (s, 1H), 8.85 (s, 1H), 7.19-7.13 (m, 2H), 6.76(m, 1H), 4.23 (s, 3H)

Example 814-((3-(Furan-3-yl)benzyl)oxy)-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazole

A flame-dried 10 ml round bottom flask containing2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo[d]oxazol-4-ol(Example 81G, 44 mg, 0.153 mmol), (3-(furan-3-yl)phenyl)methanol (80 mg,0.458 mmol) and triphenylphoshine (120 mg, 0.458 mmol) was dried underreduced pressure for 30 minutes then charged with THF (4 ml) under a N₂atmosphere. The stirred mixture was then charged with a solution ofdiisopropylazodicarboxylate (0.089 ml, 0.458 mmol) in THF (1 ml) over 30minutes. The heterogeneous reaction mixture was stirred at ambienttemperature for 2.5 hours after which it became homogeneous for about 10minutes followed by the appearance of a ppt. The reaction mixture wasdiluted with DCM, washed with sat. NaHCO₃ then brine. The organic phasewas dried (MgSO₄), filtered and concentrated to dryness. The residue wasadsorbed onto silica and purified by combiflash using a 25 g column anda gradient of 0 to 15% Et₂O in DCM to give a white solid which wastriturated with MeOH. The solid was filtered off and the resulting whitesolid was rinsed with MeOH then ether. The solid material was dissolvedin DMF and purified by prep HPLC in TFA buffered in CH₃CN/water.Fractions containing the desired product were concentrated to dryness,suspended in acetonitrile/water, frozen and lyophilized to give thetitle material as an amorphous white solid (15.2 mg, 0.034 mmol, 22.41%yield). LC (Method B): 2.322. MS(ESI) calcd. for C₂₃H₁₇N₄O₄S [M+H]⁺ m/z:445.0965. found: 445.0968. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.92 (s, 1H),8.22 (t, J=1.4 Hz, 1H), 7.79 (br. S, 1H), 7.75 (t, J=1.8 Hz, 1H), 7.62(m, 1H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, 2H), 7.07 (dd, J=2.2, 6.8 Hz,1H), 6.99 (dd, J=0.8, 2.0 Hz, 1H), 5.38 (s, 2H), 4.22 (s, 3H).

Example 822-(6-Methoxy-4-((3-(2-methoxypyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine

82A:2-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine

A mixture of 6-methylpyridazin-3-amine (1.52 g, 13.93 mmol),1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example 1D,5.00 g, 13.33 mmol) and 2-propanol (110 mL) in a 150 mL pressure flaskwas heated at 65° C. The mixture was almost homogeneous after 30 min ofheating and precipitated again after 40 min. The mixture was heated fora total of 48 h. The cooled reaction mixture was diluted withdichloromethane (600 mL), washed with saturated aqueous sodiumbicarbonate and brine and dried over anhydrous magnesium sulfate.Evaporation gave an orange brown solid which was chromatographed onsilica gel (4×9 cm, elution with 0-5% ethyl acetate-DCM) to give theproduct (3.64 g) as an orange-brown solid. The solid was boiled withethyl acetate (30 mL, partially soluble) and allowed to stand at roomtemperature for 2 h. The crystals were collected by filtration and driedovernight in vacuo to give the title material (3.440 g, 67%) as paleyellow-brown needles. LC (Method A): 2.279 min. HRMS(ESI) calcd forC₂₃H₂₀N₃O₃ [M+H]⁺ m/z 386.1505. found 386.1532. ¹H NMR (CDCl₃, 400 MHz):δ ppm 2.59 (s, 3H), 3.86 (s, 3H), 5.21 (s, 2H), 6.43 (d, J=1.96 Hz, 1H),6.75 (br d, 1H), 6.94 (d, J=9.39 Hz, 1H), 7.31-7.38 (m, 2H), 7.38-7.45(m, 2H), 7.50 (br d, J=7.43 Hz, 2H), 7.82 (d, J=9.39 Hz, 1H), 8.19 (s,1H).

82B: 6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol

A solution of2-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine(1.00 g, 2.59 mmol), in a mixture of dichloromethane (420 mL) andmethanol (150 mL) in a 1 L flask, was hydrogenated over 10% palladium oncarbon (0.30 g) under 1 atm of hydrogen for 6 h. The reaction mixturewas then maintained under vacuum for 2 min and finally was flushed withnitrogen. The catalyst was filtered and washed with warmdichloromethane-methanol (8:2, 100 mL) and the combined filtrate wasconcentrated under reduced pressure. The yellow residue was boiled with1,2-dichloroethane (30 mL) and allowed to stand at room temperature for18 h. The solid was filtered (contains methanol by NMR) and dried invacuo at 120° C. for 12 h to give the title material (0.760 g, 99%) as ayellow solid. LC (Method A): 1.844 min. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm2.54 (s, 3H), 3.77 (s, 3H), 6.28 (d, J=1.96 Hz, 1H), 6.70 (dd, J=1.96,1.17 Hz, 1H), 7.20 (d, J=9.39 Hz, 1H), 7.24 (d, J=0.78 Hz, 1H), 8.03 (d,J=9.78 Hz, 1H), 8.50 (s, 1H), 10.10 (br s, 1H).

Example 822-(6-Methoxy-4-((3-(2-methoxypyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine

In a 10 mL round-bottomed flask, a mixture of6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol (0.050g, 0.169 mmol), (3-(2-methoxypyrimidin-5-yl)phenyl)methanol (0.099 g,0.458 mmol) and triphenylphosphine (0.120 g, 0.458 mmol) was dried underhigh vacuum for 10 min. Dry THF (1.5 mL) was then added and the mixturewas sonicated for 15 min. Diisopropyl azodicarboxylate (0.090 mL, 0.463mmol) in THF (1 mL) was added dropwise on 15 min, then the yellowsolution was sonicated for 30 min and finally it was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with CH₂Cl₂,washed with saturated aqueous NaHCO₃ and brine, dried over anhydrousNa₂SO₄ and concentrated. The obtained residue was purified on the ISCOusing a 12 g SILICYCLE® column (elution with CH₂Cl₂-EtOAc) to give thetitle compound (0.040 g, 48%) as pale yellow solid, after triturationwith acetonitrile and lyophilization from acetonitrile-water. LC (MethodB): 2.319 min. HRMS(ESI): calcd for C₂₈H₂₄N₅O₄ [M+H]⁺ m/z 494.1828.found 494.1860. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.94-8.99 (m, 2H) 8.55(s, 1H) 8.01 (d, J=9.4 Hz, 1H) 7.90 (s, 1H) 7.69-7.75 (m, 1H) 7.52-7.61(m, 2H) 7.30 (s, 1H) 7.19 (d, J=9.4 Hz, 1H) 6.87-6.90 (m, 1H) 6.57-6.63(m, 1H) 5.34 (s, 2H) 3.97 (s, 3H) 3.82 (s, 3H) 2.53 (s, 3H).

Example 836-(4-((3-Fluoro-5-(2-methoxypyrimidin-5-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

83A: (3-Fluoro-5-(methoxycarbonyl)phenyl)boronic acid

To a 50 mL round-bottomed flask fitted with a reflux condenser andcharged with 3-carboxy-5-fluorophenylboronic acid (0.53 g, 2.88 mmol) inmethanol (16 mL) was added a 6 M aqueous solution of sulfuric acid (0.33mL, 1.98 mmol) and the mixture was heated to reflux overnight. Thecooled mixture was diluted with water and the product was extracted withdiethyl ether (×3). The combined organic extract was concentrated togive the title material (0.535 g, 94%) as white solid. LC (Method B):1.596 min. LCMS (APCI): calcd for C₈H₇BFO₄ [M−H]⁻ m/z 197.043. found197.2. ¹H NMR (400 MHz, acetone-d₆): δ ppm 8.34 (s, 1H) 7.80 (ddd,J=9.2, 2.7, 1.0 Hz, 1H) 7.72 (ddd, J=9.4, 2.7, 1.6 Hz, 1H) 7.56 (s, 2H)3.91 (s, 3H).

83B: Methyl and n-propyl 3-fluoro-5-(2-methoxypyrimidin-5-yl)benzoate

In a 20 mL vial, palladium(II) acetate (0.0084 g, 0.037 mmol),triphenylphosphine (0.018 g, 0.068 mmol), 2 M aqueous sodium carbonate(0.90 mL, 1.80 mmol) and water (0.6 mL, 33.3 mmol) were successivelyadded to a mixture of 5-bromo-2-methoxypyrimidine (0.246 g, 1.302 mmol)and (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (0.278 g, 1.404mmol) in 1-propanol (2.8 mL) under nitrogen. The mixture was stirred at95° C. for 1 h and kept overnight at room temperature. The mixture wasthen quenched with water and the product was extracted with EtOAc (×3).The combined organic extract was washed once with saturated aqueousNaHCO₃, once with brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was purified on the ISCO using a REDISEP® Gold 40 g column(elution with hexanes-EtOAc) to give methyl3-fluoro-5-(2-methoxypyrimidin-5-yl)benzoate (0.236 g, 69%) as a whitesolid. LC (Method B): 1.856 min. LCMS (APCI): calcd for C₁₃H₁₂FN₂O₃[M+H]⁺ m/z 263.083. found 263.1. ¹H NMR (400 MHz, acetone-d₆): δ ppm8.96 (s, 2H) 8.13 (t, J=1.4 Hz, 1H) 7.82 (ddd, J=9.6, 2.5, 1.8 Hz, 1H)7.73 (ddd, J=9.0, 2.5, 1.4 Hz, 1H) 4.03 (s, 3H) 3.94 (s, 3H). Furtherelution afforded n-propyl 3-fluoro-5-(2-methoxypyrimidin-5-yl)benzoate(0.026 g, 6.9%) as a white solid. LC (Method B): 2.119 min. LCMS (APCI):calcd for C₁₅H₁₆FN₂O₃ [M+H]⁺ m/z 291.114. found 291.2. ¹H NMR (400 MHz,acetone-d₆): δ ppm 8.96 (s, 2H) 8.14 (t, J=1.6 Hz, 1H) 7.81 (ddd, J=9.6,2.6, 1.6 Hz, 1H) 7.75 (ddd, J=9.0, 2.6, 1.4 Hz, 1H) 4.32 (t, J=6.5 Hz,2H) 4.02 (s, 3H) 1.82 (sext, J=7.1 Hz, 2H) 1.04 (t, J=7.4 Hz, 3H).

83C: (3-Fluoro-5-(2-methoxypyrimidin-5-yl)phenyl)methanol

In a 25 mL round-bottomed flask under nitrogen, lithium aluminum hydride(0.075 g, 1.976 mmol) was added portionwise over 10 min to a solution ofmethyl 3-fluoro-5-(2-methoxypyrimidin-5-yl)benzoate (0.235 g, 0.896mmol) and propyl 3-fluoro-5-(2-methoxypyrimidin-5-yl)benzoate (0.025 g,0.086 mmol) in dry THF (10 mL) at 0° C. The mixture was stirred 5 h atroom temperature and then it was quenched by the addition of 0.08 mL ofwater, followed by 0.08 mL of 15% aqueous NaOH and finally 0.24 mL ofwater. The mixture was stirred for 30 min at room temperature and thenanhydrous Na₂SO₄ was added and stirring was continued for 30 min at roomtemperature. The resulting mixture was filtered, the filter-cake waswashed with EtOAc and the filtrate was concentrated. The residue waspurified on the ISCO using a 40 g SILICYCLE® column (elution withhexanes-EtOAc) to give the title material (0.048 g, 21%) as a whitesolid. LC (Method B): 1.557 min. LCMS (APCI): calcd for C₁₂H₁₂FN₂O₂[M+H]⁺ m/z 235.088. found 235.2. ¹H NMR (400 MHz, acetone-d₆): δ ppm8.88 (s, 2H) 7.49-7.53 (m, 1H) 7.34-7.41 (m, 1H) 7.17-7.25 (m, 1H) 4.74(d, J=5.9 Hz, 2H) 4.45 (t, J=5.9 Hz, 1H) 4.01 (s, 3H).

Example 836-(4-((3-Fluoro-5-(2-methoxypyrimidin-5-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

In a 20 mL vial, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.040 g, 0.126 mmol) and(3-fluoro-5-(2-methoxypyrimidin-5-yl)phenyl)methanol (0.048 g, 0.205mmol) was dried for 5 min under high vacuum. Under a nitrogenatmosphere, tri-n-butylphosphine (0.080 mL, 0.324 mmol) and THF (2 mL)were added and the mixture was sonicated for 10 min. A solution of1,1′-(azodicarbonyl)dipiperidine (0.081 g, 0.321 mmol) in THF (1 mL) wasthen added dropwise on 10 min, the mixture was sonicated for 30 min andthen stirred for 1 h at room temperature. The resulting mixture wasdiluted with CH₂Cl₂ and washed once with saturated aqueous NaHCO₃, oncewith brine, dried on anhydrous Na₂SO₄ and concentrated. The residue waspurified on the ISCO using a REDISEP® Gold 12 g column (elution withCH₂Cl₂-EtOAc) to give the title compound (0.048 g, 71%) as a whitesolid, after trituration with acetonitrile and lyophilization fromacetonitrile/water. LC (Method B): 2.394 min. HRMS(ESI): calcd forC₂₆H₂₁FN₅O₅S [M+H]⁺ m/z 534.1247. found 534.1259. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 9.01 (s, 2H) 8.38 (s, 1H) 7.76 (t, J=1.6 Hz, 1H)7.61-7.68 (m, 1H) 7.37-7.43 (m, 1H) 7.06 (d, J=0.8 Hz, 1H) 6.85 (dd,J=1.6, 0.8 Hz, 1H) 6.56 (d, J=2.0 Hz, 1H) 5.33 (s, 2H) 4.20 (s, 3H) 3.98(s, 3H) 3.80 (s, 3H).

Example 845-(3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)picolinicacid

In a 10 mL round-bottomed flask, tert-butyl5-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)picolinate(Example 60, 0.023 g, 0.039 mmol) was stirred in dichloromethane (0.5mL) and trifluoroacetic acid (0.5 mL) for 5 h at room temperature.Toluene was then added and the mixture was concentrated under reducedpressure. This afforded the title compound (TFA salt, 0.025 g, 91%) as awhite solid, after lyophilization from acetonitrile-water. LC (MethodB): 2.313 min. LCMS (APCI): calcd for C₂₇H₂₁N₄O₆S [M+H]⁺ m/z 529.118.found 529.2. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 9.05 (dd, J=2.3, 0.8 Hz,1H) 8.38 (s, 1H) 8.30 (dd, J=7.8, 2.3 Hz, 1H) 8.14 (dd, J=8.2, 0.8 Hz,1H) 7.96 (t, J=1.8 Hz, 1H) 7.80 (dt, J=7.3, 1.6 Hz, 1H) 7.56-7.67 (m,2H) 7.02 (d, J=0.8 Hz, 1H) 6.84 (dd, J=2.0, 0.8 Hz, 1H) 6.58 (d, J=2.0Hz, 1H) 5.35 (s, 2H) 4.20 (s, 3H) 3.80 (s, 3H).

Example 855-(3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)-N-(2-methoxyethyl)-N-methylpicolinamide

In a 10 mL round-bottomed flask under nitrogen, DIEA (0.025 mL, 0.143mmol) was added to a stirred solution of5-(3-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)picolinicacid, TFA salt (0.025 g, 0.039 mmol) and 2-methoxy-N-methylethanamine(0.005 mL, 0.047 mmol) in DMF (0.5 mL) and the solution was stirred atroom temperature for 5 min. HATU (0.016 g, 0.042 mmol) was then addedand the reaction was stirred at room temperature for 45 min. Thereaction mixture was then quenched with a few drops of acetic acid, thesample was diluted with DMSO and the solution was purified usingpreparative HPLC (Method X: ZORBAX® SB-C18 column 21.2×100 mm, elutedwith MeOH-water-0.1% TFA. Gradient: Isocratic 50% for 3 min, thengradient to 100% MeOH over 8 min). The product-containing fractions wereevaporated and the title compound (0.014 g, 60%) was obtained asyellowish solid after lyophilization of the residue fromacetonitrile-water. LC (Method B): 2.347 min. HRMS(ESI): calcd forC₃₁H₃₀N₅O₆S [M+H]⁺ m/z 600.1917. found 600.1948. ¹H NMR (400 MHz,acetone-d₆): δ ppm 8.91 (dd, J=8.8, 1.8 Hz, 1H) 8.21 (dt, J=8.2, 2.3 Hz,1H) 8.10 (s, 1H) 7.97 (t, J=1.8 Hz, 1H) 7.73-7.78 (m, 1H) 7.64-7.73 (m,2H) 7.57-7.63 (m, 1H) 7.06 (s, 1H) 6.77 (dd, J=2.0, 0.8 Hz, 1H) 6.56 (d,J=1.6 Hz, 1H) 5.39 (s, 2H) 4.26 (s, 3H) 3.85 (s, 3H) 3.54-3.74 (m, 4H)3.09-3.37 (m, 6H).

Example 862-Methoxy-6-(6-methoxy-4-((3-(5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

86A. 1-(6-Bromopyridin-3-yl)ethanol

In a 50 ml, round-bottomed flask under nitrogen, sodium borohydride(0.390 g, 10.31 mmol) was added portionwise on 5 min to a solution of5-acetyl-2-bromopyridine (0.515 g, 2.57 mmol) in 2-propanol (10 mL) andwater (4 mL) and the mixture was stirred at room temperature for 30 min.The mixture was then concentrated in vacuo and water was added to theconcentrate. The mixture was extracted with ethyl acetate (×3) and thecombined organic extract was dried over anhydrous Na₂SO₄ andconcentrated. The obtained residue was purified on the ISCO using a 25 gSILICYCLE® column (elution with hexanes-EtOAc) to give the titlematerial (0.470 g, 90%) as colorless oil. LC (Method B): 1.233 min. LCMS(APCI): calcd for C₇H₉BrNO [M+H]⁺ m/z 201.986. found 202.0. ¹H NMR (400MHz, acetone-d₆): δ ppm 8.38 (d, J=2.7 Hz, 1H) 7.71-7.77 (m, 1H) 7.54(d, J=8.2 Hz, 1H) 4.92 (q, J=6.7 Hz, 1H) 1.43 (d, J=6.7 Hz, 3H).

86B. 2-Bromo-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine

In a 20 mL vial under nitrogen, p-toluenesulfonic acid monohydrate(0.007 g, 0.037 mmol) was added to a solution of1-(6-bromopyridin-3-yl)ethanol (0.259 g, 1.282 mmol) and3,4-dihydro-2H-pyran (0.58 mL, 6.36 mmol) in dichloromethane (5 mL) andthe mixture was stirred for 1 h at room temperature. The mixture wasthen diluted with dichloromethane, the organic layer was separated,washed once with saturated aqueous NaHCO₃, once with brine, dried overanhydrous Na₂SO₄ and concentrated. The obtained residue was purified onthe ISCO using a REDISEP® Gold 24 g column (elution with hexanes-EtOAc)to give the title material (0.355 g, 97%) as colorless oil which was amixture of diastereomers. LC (Method B): 2.014 min. LCMS (APCI): calcdfor C₁₂H₁₇BrNO₂ [M+H]⁺ m/z 286.044. found 286.0. ¹H NMR (400 MHz,acetone-d₆): δ ppm 8.41-7.55 (3H) 4.93-3.31 (4H) 1.85-1.48 (6H)1.46-1.42 (3H).

86C.(3-(5-(1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)phenyl)methanol

In a 20 mL vial, palladium(II) acetate (0.007 g, 0.030 mmol),triphenylphosphine (0.016 g, 0.059 mmol), aqueous sodium carbonate (2 M,0.86 mL, 1.72 mmol) and water (0.4 mL, 22.2 mmol) were successivelyadded to a mixture of2-bromo-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine (0.353 g,1.234 mmol) and (3-(hydroxymethyl)phenyl)-boronic acid (0.207 g, 1.362mmol) in 1-propanol (2.1 mL) under nitrogen. The mixture was stirred at95° C. for 1 h and then the cooled mixture was quenched with water andthe product was extracted with EtOAc (×3). The combined organic extractwas washed once with saturated aqueous NaHCO₃, once with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified on theISCO using a REDISEP® Gold 40 g column (elution with hexanes-EtOAc) togive the title material (0.288 g, 75%) as a colorless oil which was amixture of diastereomers. LC (Method B): 1.603 min, 1.673 min. LCMS(APCI): calcd for C₁₉H₂₄NO₃ [M+H]⁺ m/z 314.175. found 314.2. ¹H NMR (400MHz, acetone-d₆): δ ppm 8.70-740 (m, 7H) 4.98-3.33 (m, 7H) 1.90-1.47 (m,9H).

Example 862-Methoxy-6-(6-methoxy-4-((3-(5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 35 mL round-bottomed flask, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.199 g, 0.627 mmol) and(3-(5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)phenyl)methanol(0.288 g, 0.919 mmol) was dried under high vacuum for 15 min and thenthe flask was flushed with nitrogen. Under a nitrogen atmosphere,tri-n-butylphosphine (0.38 mL, 1.540 mmol) and dry THF (10 mL) were thenadded. A solution of 1,1′-(azodicarbonyl)dipiperidine (0.394 g, 1.562mmol) in THF (6 mL) was then added dropwise over 10 min and the mixturewas stirred at room temperature for 3 h. The reaction mixture wassubsequently diluted with CH₂Cl₂ and washed once with saturated aqueousNaHCO₃, once with brine, dried over anhydrous Na₂SO₄ and concentrated.The obtained residue was purified on the ISCO using a 80 g SILICYCLE®column (elution with CH₂Cl₂-EtOAc) to give the title material (0.273 g,71%) as a beige solid which was a mixture of diastereomers. LC (MethodB): 2.361 min, 2.410 min. LCMS (APCI): calcd for C₃₃H₃₃N₄O₆S [M+H]⁺ m/z613.212. found 613.2. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.68-6.56 (m,11H) 5.35 (m, 3H) 4.94-3.43 (m, 4H) 4.20 (s, 3H) 3.79 (s, 3H) 1.75-1.43(m, 9H).

Example 871-(6-(3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)pyridin-3-yl)ethanol

In a 20 mL vial,2-methoxy-6-(6-methoxy-4-((3-(5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-2-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.100 g, 0.163 mmol) was stirred overnight at 45° C. in 5.6 mL of a4:2:1 mixture of acetic acid-THF-water. The cooled mixture was dilutedwith ethyl acetate, washed twice with saturated aqueous NaHCO₃, oncewith brine, dried over anhydrous Na₂SO₄ and concentrated. The obtainedresidue was purified on the ISCO using a REDISEP® Gold 12 g column(elution with CH₂Cl₂-EtOAc) to give the title material (0.097 g, 88%) aswhite solid after lyophilization from acetonitrile-water. LC (Method B):2.157 min. HRMS(ESI): calcd for C₂₈H₂₅N₄O₅S [M+H]⁺ m/z 529.1546. found529.1581. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.64 (d, J=2.3 Hz, 1H) 8.38(s, 1H) 8.20-8.25 (m, 1H) 8.03 (dt, J=7.4, 1.6 Hz, 1H) 7.94 (d, J=8.2Hz, 1H) 7.84 (dd, J=8.4, 2.2 Hz, 1H) 7.49-7.60 (m, 2H) 7.00 (s, 1H)6.80-6.87 (m, 1H) 6.57 (d, J=1.6 Hz, 1H) 5.31-5.39 (m, 3H) 4.83 (dq,J=6.5, 4.5 Hz, 1H) 4.20 (s, 3H) 3.79 (s, 3H) 1.39 (d, J=6.3 Hz, 3H).

Preparation of Benzylic Alcohols

The following additional benzylic alcohols were prepared according tothe procedures described in Example 86 using(3-(hydroxymethyl)phenyl)boronic acid and the corresponding bromides orchlorides and were employed in preparing compounds of the Examples asindicated.

Structure (Employed in Calc. LCMS HPLC preparation of Example Calc.[M]⁻- LCMS [M]⁻- Retention compound [M + H]⁺ C₅H₉O [M + H]⁺ C₅H₉O Time(Min)/ as indicated) Formula m/z m/z m/z m/z Method NMR

C₁₈H₂₀O₃ 199.077 199.0 2.149/B ¹H NMR (400 MHz, acetone-d₆): δ ppm7.60-7.63 (m, 1H) 7.55-7.60 (m, 2H) 7.48 (dt, J = 7.8, 1.6 Hz, 1H) 7.38(t, J = 7.6 Hz, 1H) 7.29-7.33 (m, 1H) 7.10-7.16 (m, 2H) 5.50 (t, J = 3.3Hz, 1H) 4.69 (d, J = 5.8 Hz, 2H) 4.20 (t, J = 5.7 Hz, 1H) 3.87 (ddd, J =11.3, 9.2, 3.3 Hz, 1H) 3.59 (dtd, J = 11.4, 4.3, 4.3, 1.2 Hz, 2H)1.93-2.03 (m, 1H) 1.77-1.92 (m, 2H) 1.53-1.73 (m, 3H).

C₁₇H₁₉NO₃ 286.144 286.0 1.658/B ¹H NMR (400 MHz, acetone-d₆): δ ppm8.39-8.46 (m, 1H) 8.06 (s, 1H) 7.91 (dt, J = 7.4, 1.6 Hz, 1H) 7.82-7.88(m, 1H) 7.53 (dd, J = 8.6, 2.7 Hz, 1H) 7.32-7.44 (m, 2H) 5.58 (t, J =3.1 Hz, 1H) 4.71 (d, J = 6.2 Hz, 2 H) 4.22 (t, J = 5.9 Hz, 1H) 3.86(ddd, J = 11.2, 9.5, 3.1 Hz, 1H) 3.57-3.67 (m, 1H) 1.81-2.03 (m, 3H)1.55-1.76 (m, 3H).

Examples 88 to 91

The following additional Examples have been prepared, isolated andcharacterized using the methods disclosed in Examples 86 and 87employing the appropriate benzylic alcohol set out hereinbefore.

HPLC Retention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 88

C₃₂H₂₉N₃O₆S 584.1855 2.663/B 584.1863 ¹H NMR (400 MHz, DMSO- d₆): δ ppm8.38 (s, 1H) 7.74 (s, 1H) 7.56-7.65 (m, 3H) 7.42- 7.52 (m, 2H) 7.08-7.16(m, 2H) 6.99 (s, 1H) 6.81-6.85 (m, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.52 (t,J = 3.3 Hz, 1H) 5.31 (s, 2H) 4.20 (s, 3H) 3.72- 3.82 (m, 4H) 3.52-3.61(m, 1H) 1.69- 1.96 (m, 3H) 1.48-1.69 (m, 3H). 89

C₃₁H₂₈N₄O₆S 585.1808 2.396/B 585.1821 ¹H NMR (400 MHz, DMSO- d6): δ ppm8.43 (d, J = 2.3 Hz, 1H) 8.38 (s, 1H) 8.17 (s, 1H) 7.98 (dt, J = 6.8,2.1 Hz, 1H) 7.93 (d, J = 9.0 Hz, 1H) 7.56 (dd, J = 8.8, 2.9 Hz, 1H)7.47-7.54 (m, 2H) 7.00 (d, J = 0.8 Hz, 1H) 6.83 (dd, J = 2.0, 0.8 Hz,1H) 6.56 (d, J = 1.6 Hz, 1H) 5.63 (t, J = 3.1 Hz, 1H) 5.33 (s, 2H) 4.20(s, 3H) 3.79 (s, 3H) 3.73-3.78 (m, 1H) 3.55-3.63 (m, 1H) 1.72-1.97 (m,3H) 1.48-1.71 (m, 3H). 90

C₂₇H₂₁N₃O₅S 500.1275 2.388/B 500.1292 ¹H NMR (400 MHz, DMSO- d₆): δ ppm9.56 (s, 1H) 8.38 (s, 1H) 7.70 (s, 1H) 7.55 (dt, J = 7.3, 1.6 Hz, 1H)7.48-7.52 (m, 2H) 7.39-7.47 (m, 2H) 6.99 (s, 1H) 6.83-6.88 (m, 2H) 6.82-6.83 (m, 1H) 6.56 (d, J = 2.0 Hz, 1H) 5.30 (s, 2 H) 4.20 (s, 3H) 3.79(s, 3H). 91

C₂₆H₂₀N₄O₅S 501.1227 2.155/B 501.1258 ¹H NMR (400 MHz, DMSO- d₆): δ ppm10.09 (br s, 1H) 8.38 (s, 1H) 8.22 (d, J = 2.3 Hz, 1H) 8.12 (s, 1H) 7.93(ddd, J = 5.6, 3.4, 2.0 Hz, 1H) 7.82 (d, J = 8.6 Hz, 1H) 7.45-7.51 (m,2H) 7.25 (dd, J = 8.6, 2.7 Hz, 1H) 6.99 (d, J = 0.8 Hz, 1H) 6.83 (dd, J= 1.8, 1.0 Hz, 1H) 6.55 (d, J = 2.0 Hz, 1H) 5.32 (s, 2H) 4.20 (s, 3H)3.79 (s, 3H).

Example 922-Methoxy-6-(6-methoxy-4-((3-(tetrahydro-2H-pyran-4-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

92A. (3-(3,6-Dihydro-2H-pyran-4-yl)phenyl)methanol

In a 50 mL round-bottomed flask under nitrogen, a solution ofn-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was addeddropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF(5 mL) at 0° C. and the resulting mixture was stirred for 15 min. Thereaction mixture was then cooled to −78° C. and a solution ofdihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) wasslowly added and the mixture was at −78° C. for another 2 h. To thismixture was added a solution of2-(N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g,2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed towarm to 0° C. and stirred for 3 h. The reaction was then quenched withwater (15 mL) and the mixture was extracted with Et₂O (×3). The combinedorganic extract was washed successively with 15% aqueous NaOH and brineand then it was dried over anhydrous Na₂SO₄, filtered and concentrated.The crude product was chromatographed on a silica gel column (22 mm×80mm) which was eluted with 0 to 20% EtOAc in hexanes. This afforded3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53%) as acolorless oil which was used as such in the following step. ¹H NMR (400MHz, acetone-d₆): δ ppm 6.01 (tt, J=2.8, 1.5 Hz, 1H) 4.25 (q, J=3.0 Hz,2H) 3.88 (t, J=5.5 Hz, 2H) 2.48 (ttd, J=5.5, 2.8, 1.4 Hz, 2H). In a 25mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride(0.270 g, 4.65 mmol) were added to a solution of(3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5ml) and the flask was evacuated and purged with nitrogen three times.Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethanecomplex (0.024 g, 0.029 mmol) was then added in one portion and themixture was stirred at room temperature for 66 h. The resulting mixturewas diluted with ethyl acetate, filtered through CELITE® andconcentrated. The residue was purified on the ISCO using a REDISEP® Gold24 g column (elution with hexanes-EtOAc) to give the title compound(0.131 g, 52%) as yellowish oil. LC (Method B): 1.614 min LCMS (APCI):calcd for C₁₂H₁₃O [M+H]⁺-H₂O m/z 173.096. found 173.2. ¹H NMR (400 MHz,acetone-d₆): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J=3.0, 1.5Hz, 1H) 4.64 (d, J=5.9 Hz, 2H) 4.24 (q, J=3.0 Hz, 2H) 4.17 (t, J=5.7 Hz,1H) 3.86 (t, J=5.5 Hz, 2H) 2.49 (ttd, J=5.4, 2.8, 1.6 Hz, 2H).

92B. (3-(Tetrahydro-2H-pyran-4-yl)phenyl)methanol

In a 25 mL round-bottomed flask, a mixture of(3-(3,6-dihydro-2H-pyran-4-yl)phenyl)methanol (0.101 g, 0.531 mmol) and5% palladium on carbon (0.033 g, 0.016 mmol) in ethanol (10 mL) washydrogenated (1 atm H₂) for 45 min. The mixture was filtered throughCELITE®, the filter-cake was rinsed with ethyl acetate and the filtratewas concentrated. The residue was purified on the ISCO using a REDISEP®Gold 12 g column (elution with hexanes-EtOAc) to give the title compound(0.070 g, 69%) as a yellowish oil. LC (Method B): 2.157 min HRMS(ESI):calcd for C₂₈H₂₅N₄O₅S [M+H]⁺ m/z 529.1546. found 529.1581. ¹H NMR (400MHz, acetone-d₆): δ ppm 7.22-7.30 (m, 2H) 7.16-7.21 (m, 1H) 7.13 (dt,J=7.5, 1.3 Hz, 1H) 4.62 (d, J=5.9 Hz, 2H) 4.11 (t, J=5.9 Hz, 1H) 3.97(dt, J=11.3, 3.1 Hz, 2H) 3.42-3.52 (m, 2H) 2.75-2.78 (m, 1H) 1.69-1.77(m, 4H).

Example 922-Methoxy-6-(6-methoxy-4-((3-(tetrahydro-2H-pyran-4-yl)benzyl)oxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

In a 35 mL round-bottomed flask under nitrogen, a solution of1,1′-(azodicarbonyl)dipiperidine (0.141 g, 0.559 mmol) in THF (2.5 mL)was added dropwise over 10 min to a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.073 g, 0.230 mmol),(3-(tetrahydro-2H-pyran-4-yl)phenyl)methanol (0.070 g, 0.364 mmol) andtri-n-butylphosphine (0.145 mL, 0.588 mmol) in dry THF (3 mL) and themixture was stirred at room temperature for 3 h. The reaction mixturewas then diluted with CH₂Cl₂, washed once with saturated aqueous NaHCO₃,once with brine, dried on anhydrous Na₂SO₄ and concentrated. The residuewas purified on the ISCO using a REDISEP® Gold 24 g column (elution withCH₂Cl₂-EtOAc) to give the title compound (0.066 g, 58%) as white solid,after lyophilization from acetonitrile-water. LC (Method B): 2.436 minHRMS(ESI): calcd for C₂₆H₂₆N₃O₅S [M+H]⁺ m/z 492.1593. found 492.1633. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 8.38 (s, 1H) 7.40 (s, 1H) 7.32-7.38 (m,2H), 7.22-7.27 (m, 1H) 6.97 (s, 1H) 6.80-6.85 (m, 1H) 6.54 (d, J=2.0 Hz,1H) 5.22 (s, 2H) 4.20 (s, 3H) 3.90-3.99 (m, 2H) 3.79 (s, 3H) 3.38-3.49(m, 2H) 2.80 (tt, J=10.6, 5.3 Hz, 1H) 1.60-1.76 (m, 4H).

Preparation of Alcohols

The following additional alcohols were prepared according to theprocedures described in Example 92.

Structure LCMS HPLC Retention (Employed in preparation Calc. [M + H]⁺[M + H]⁺ —H₂O Time (Min)/ of compound as indicated) Formula —H₂O m/z m/zMethod NMR

C₁₃H₁₆O 171.1168 171.2 2.132/B ¹H NMR (400 MHz, acetone-d₆): δ ppm 7.40(s, 1 H) 7.24-7.29 (m, 2H) 7.17- 7.24 (m, 1H) 6.12 (tt, J = 4.1, 1.7 Hz,1H) 4.62 (d, J = 6.3 Hz, 2H) 4.11 (t, J = 5.9 Hz, 1H) 2.36-2.44 (m, 2H)2.15- 2.23 (m, 2H) 1.72-1.81 (m, 2H) 1.60- 1.69 (m, 2H).

C₁₃H₁₈O 173.1325 173.2 ¹H NMR (400 MHz, acetone-d₆): δ ppm 7.19-7.26 (m,2H) 7.12-7.17 (m, 1H) 7.09 (dt, J = 7.4, 1.6 Hz, 1H) 4.60 (d, J = 5.9Hz, 1H) 4.07 (t, J = 5.7 Hz, 1H) 2.43-2.57 (m, 1H) 1.78-1.87 (m, 4H)1.69-1.78 (m, 1H) 1.34-1.54 (m, 4H) 1.23-1.34 (m, 1H).

Examples 93 to 95

The following additional Examples have been prepared, isolated andcharacterized using the method disclosed in Examples 92 employing theappropriate alcohol set out hereinbefore.

HPLC Retention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 93

C₂₆H₂₃N₃O₅S 490.1437 2.449/B 490.1453 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.38 (s, 1 H) 7.58 (s, 1 H) 7.35-7.46 (m, 3 H) 6.98 (d, J = 0.8 Hz, 1 H)6.83 (dd, J = 1.8, 1.0 Hz, 1 H) 6.53 (d, J = 2.0 Hz, 1 H) 6.25-6.32 (m,1 H) 5.25 (s, 2 H) 4.23 (q, J = 2.7 Hz, 2 H) 4.20 (s, 3 H) 3.83 (t, J =5.5 Hz, 2 H) 3.79 (s, 3 H) 2.43- 2.48 (m, 2 H) 94

C₂₇H₂₅N₃O₄S 488.1644 2.726/B 488.1651 ¹H NMR (400 MHz, DMSO- d₆) δ ppm8.38 (s, 1H) 7.52 (s, 1H) 7.33-7.40 (m, 3H) 6.97 (s, 1H) 6.80- 6.85 (m,1H) 6.53 (d, J = 1.6 Hz, 1H) 6.18 (tt, J = 3.8, 2.1 Hz, 1H) 5.24 (s, 2H)4.20 (s, 3H) 3.79 (s, 3H) 2.34-2.43 (m, 2H) 2.13- 2.23 (m, 2H) 1.67-1.79(m, 2H) 1.55- 1.66 (m, 2H). 95

C₂₇H₂₇N₃O₄S 490.1801 2.751/B 490.1809 ¹H NMR (400 MHz, DMSO- d₆): δ ppm8.38 (s, 1H) 7.28- 7.38 (m, 3H) 7.20 (dt, J = 6.0, 2.1 Hz, 1H) 6.93-6.98(m, 1H) 6.80- 6.85 (m, 1H) 6.53 (d, J = 2.0 Hz, 1H) 5.21 (s, 2H) 4.20(s, 3H) 3.79 (s, 3H) 2.52-2.56 (m, 1H) 1.79 (d, J = 8.6 Hz, 4H)1.64-1.74 (m, 1H) 1.30- 1.49 (m, 4H) 1.14-1.30 (m, 1H).

Example 964-(6-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)pyridin-2-yl)-N,N-dimethylbenzamide

96A. 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

In a 25 mL round-bottomed flask under nitrogen,tert-butylchlorodimethylsilane (1.54 g, 10.22 mmol) was added to asolution of (6-bromopyridin-2-yl)methanol (1.27 g, 6.75 mmol) andimidazole (0.545 g, 8.01 mmol) in DMF (8 mL) and the mixture was stirredat room temperature for 1.5 h. The mixture was then diluted with waterand the product was extracted with ethyl acetate (×3). The combinedorganic extract was washed once with water, once with brine, dried overanhydrous Na₂SO₄ and concentrated. The obtained residue was purified onthe ISCO using a SILICYCLE® 80 g column (elution with hexanes-EtOAc) togive the title material (1.97 g, 96%) as colorless liquid. LC (MethodB): 2.422 min. LCMS (APCI): calcd for C₁₂H₂₁BrNOSi [M+H]⁺ m/z 302.057.found 302.0. ¹H NMR (400 MHz, MeOH-d₄): δ 7.71 (t, J=7.83 Hz, 1H), 7.51(dd, J=0.78, 7.83 Hz, 1H), 7.46 (dd, J=0.78, 7.83 Hz, 1H), 4.76 (s, 2H),0.97 (s, 9H), 0.14 (s, 6H).

96B.4-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-N,N-dimethylbenzamide

In a 75 mL pressure vessel, a solution of2-bromo-6-(((tert-butyldimethylsilyl)oxy)-methyl)pyridine (0.197 g,0.652 mmol), (4-(dimethylcarbamoyl)phenyl)boronic acid (0.197 g, 1.021mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (0.032 g, 0.039 mmol) in a mixture oftoluene (6 mL) and ethanol (2 mL) was purged with a stream of nitrogenbubbles for 15 min. To this mixture was added aqueous sodium carbonate(2 M, 0.41 mL, 0.82 mmol) and the mixture was heated at 95° C.overnight. The cooled mixture was diluted with water and the product wasextracted with ethyl acetate (×3). The combined organic extract waswashed once with saturated aqueous NaHCO₃, once with brine, dried overanhydrous Na₂SO₄ and concentrated. The obtained residue was purified onthe ISCO using an Innoflash 25 g column (elution with CH₂Cl₂-EtOAc) togive the title material (0.214 g, 89%) as yellow oil. LC (Method B):2.330 min LCMS (APCI): calcd for C₂₁H₃₁N₂O₂Si [M+H]⁺ m/z 371.215. found371.2. ¹H NMR (400 MHz, MeOH-d₄): δ 8.09 (d, J=7.83 Hz, 2H), 7.91 (t,J=7.83 Hz, 1H), 7.77 (d, J=7.83 Hz, 1H), 7.49-7.58 (m, 3H), 4.89 (s,2H), 3.13 (s, 3H), 3.05 (s, 3H), 0.99 (s, 9H), 0.17 (s, 6H).

96C. 4-(6-(Hydroxymethyl)pyridin-2-yl)-N,N-dimethylbenzamide

In a 25 mL round-bottomed flask, a solution of4-(6-(((tert-butyldimethylsilyl)oxy)-methyl)pyridin-2-yl)-N,N-dimethylbenzamide(0.214 g, 0.578 mmol) and triethylamine trihydrofluoride (0.45 mL, 2.76mmol) in dry THF (8 mL) was stirred at room temperature under nitrogenfor 19 h. The reaction was then quenched by the addition of 5 mL ofmethanol and the mixture was concentrated. The concentrate was dilutedwith ethyl acetate and the solution was washed once with saturatedaqueous NaHCO₃, once with brine, dried on anhydrous Na₂SO₄ andconcentrated. The obtained residue was purified on the ISCO using anInnoflash 12 g column (elution with CH₂Cl₂-EtOAc) to give the titlecompound (0.121 g, 82%) as white solid. LC (Method B): 1.110 min LCMS(APCI): calcd for C₁₅H₁₇N₂O₂ [M+H]⁺ m/z 257.129. found 257.2. ¹H NMR(400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 8.15-8.21 (m, 2H), 7.96-8.02 (m,2H), 7.57-7.64 (m, 1H), 7.50-7.57 (m, 2H), 7.07 (s, 1H), 6.85 (dd,J=0.98, 1.76 Hz, 1H), 6.58 (d, J=1.96 Hz, 1H), 5.42 (s, 2H), 4.21 (s,3H), 3.79 (s, 3H), 3.01 (br s, 3H), 2.95 (br s, 3H).

Example 964-(6-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)pyridin-2-yl)-N,N-dimethylbenzamide

In a 25 mL round-bottomed flask, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.050 g, 0.158 mmol),4-(6-(hydroxymethyl)pyridin-2-yl)-N,N-dimethylbenzamide (0.051 g, 0.199mmol) and tri-n-butylphosphine (0.12 mL, 0.486 mmol) was kept under highvacuum for 10 min, back-filled with nitrogen and suspended in dry THF(1.5 mL). A solution of 1,1′-(azodicarbonyl)dipiperidine (0.095 g, 0.377mmol) in THF (1.5 mL) was then added dropwise on 10 min and the mixturewas stirred at room temperature for 4.5 h. The reaction mixture was thendiluted with CH₂Cl₂ and washed once with saturated aqueous NaHCO₃, oncewith brine, dried on anhydrous Na₂SO₄ and concentrated. The residue waspurified on the ISCO using a REDISEP® Gold 24 g column (elution withCH₂Cl₂-EtOAc) to give the title compound (0.068 g, 78%) as a whitesolid, after lyophilization from acetonitrile-water. LC (Method B):2.237 min. HRMS(ESI): calcd for C₂₉H₂₆N₅O₅S [M+H]⁺ m/z 556.1655. found556.1649. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 8.15-8.21 (m, 2H),7.96-8.02 (m, 2H), 7.57-7.64 (m, 1H), 7.50-7.57 (m, 2H), 7.07 (s, 1H),6.85 (dd, J=0.98, 1.76 Hz, 1H), 6.58 (d, J=1.96 Hz, 1H), 5.42 (s, 2H),4.21 (s, 3H), 3.79 (s, 3H), 3.01 (br s, 3H), 2.95 (br s, 3H).

Example 976-(4-((2-(2-Fluoropyridin-4-yl)pyrimidin-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

97A. Methyl 2-(2-fluoropyridin-4-yl)pyrimidine-4-carboxylate

In a 15 mL pressure vessel, a solution of methyl2-chloropyrimidine-4-carboxylate (0.048 g, 0.278 mmol),(2-fluoropyridin-4-yl)boronic acid (0.060 g, 0.426 mmol) andPd(dppf)Cl₂.DCM (0.013 g, 0.016 mmol) in a mixture of toluene (4 mL) andethanol (3 mL) was degassed under high vacuum and back-filled withnitrogen three times. An aqueous solution of sodium carbonate (2 M, 0.18mL, 0.360 mmol) was then added and the mixture was heated at 105° C.overnight. The cooled mixture was diluted with water and the resultingmixture was washed with ethyl acetate (×3). The aqueous layer wasseparated, acidified to pH 1 with 1 M hydrochloric acid and extractedwith ethyl acetate (×1) and then dichloromethane (×2). The combinedorganic extract was washed once with brine, dried over anhydrous Na₂SO₄and concentrated. The crude residue was taken up in THF (3 mL) andtreated with a solution of diazomethane (0.77 M in Et₂O, 1 mL, 0.77mmol) and the mixture was stirred at room temperature for 64 h. Thevolatiles were then removed in vacuo and the residue was purified on theISCO using a REDISEP® 4 g column (elution with hexanes-EtOAc) to givethe title compound (0.020 g, 31%) as a white solid. LC (Method B): 1.691min. LCMS (APCI): calcd for C₁₁H₉FN₃O₂ [M+H]⁺ m/z 234.067. found 234.2.¹H NMR (400 MHz, MeOH-d₄): δ 9.20 (d, J=4.70 Hz, 1H), 8.33-8.41 (m, 2H),8.10 (s, 1H), 8.08 (d, J=4.70 Hz, 1H), 4.06 (s, 3H).

97B. (2-(2-Fluoropyridin-4-yl)pyrimidin-4-yl)methanol

In a 25 mL round-bottomed flask under nitrogen at 0° C., sodiumborohydride (0.007 g, 0.185 mmol) and methanol (0.01 mL, 0.25 mmol) wereadded to a solution of methyl2-(2-fluoropyridin-4-yl)pyrimidine-4-carboxylate (0.020 g, 0.086 mmol)in THF (2 mL) and the mixture was then stirred at room temperature for18 h. The mixture was re-cooled in an ice bath and quenched by thedropwise addition of saturated aqueous NH₄Cl. The product was extractedwith ethyl acetate (×3) and the combined organic extract was washed oncewith brine, dried over anhydrous Na₂SO₄ and concentrated. The cruderesidue was purified on the ISCO using a REDISEP® 4 g column (elutionwith hexanes-EtOAc) to give the title compound (0.012 g, 65%) as a whitesolid. LC (Method B): 1.406 min. LCMS (APCI): calcd for C₁₀H₉FN₃O [M+H]⁺m/z 206.072. found 206.2. ¹H NMR (400 MHz, MeOH-d₄): δ 8.92 (d, J=5.09Hz, 1H), 8.35 (d, J=5.48 Hz, 1H), 8.29 (td, J=1.47, 5.28 Hz, 1H), 8.01(s, 1H), 7.64 (d, J=5.09 Hz, 1H), 4.79 (s, 2H).

Example 976-(4-((2-(2-fluoropyridin-4-yl)pyrimidin-4-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

In a 25 mL round-bottomed flask, a mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.014 g, 0.044 mmol),(2-(2-fluoropyridin-4-yl)pyrimidin-4-yl)methanol (0.011 g, 0.054 mmol)and tri-n-butylphosphine (0.040 mL, 0.162 mmol) was kept under highvacuum for 10 min, then the flask was back-filled with nitrogen and dryTHF (1 mL) was added. A solution of 1,1′-(azodicarbonyl)dipiperidine(0.035 g, 0.139 mmol) in dry THF (1 mL) was then added dropwise on 10min and the mixture was stirred at room temperature for 17 h. Thereaction mixture was then diluted with CH₂Cl₂ and the mixture was washedonce with saturated aqueous NaHCO₃, once with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified twice on theISCO using a REDISEP® Gold 12 g column (elution with CH₂Cl₂-EtOAc, thenwith hexanes-EtOAc) to give the title compound (0.0057 g, 26%) as awhite solid, after lyophilization from acetonitrile-water. LC (MethodB): 2.507 min. HRMS(ESI): calcd for C₂₄H₁₈FN₆O₄S [M+H]⁺ m/z 505.1094.found 505.1092. ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (d, J=5.09 Hz, 1H),8.47 (d, J=5.09 Hz, 1H), 8.40 (s, 1H), 8.24 (td, J=1.66, 5.28 Hz, 1H),7.94 (s, 1H), 7.85 (d, J=5.09 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.58(d, J=1.57 Hz, 1H), 5.50 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H).

Preparation of Alcohols

The following additional intermediate alcohols were prepared accordingto the procedures described in Example 97.

Structure Calc. LCMS HPLC Retention (Employed in preparation of [M + H]⁺[M + H]⁺ Time (Min)/ Example as indicated) Formula m/z m/z Method NMR

C14H15N3O2 258.1237 258.2 1.362/B

C12H9N3O 212.0818 212.2 1.581/B ¹H NMR (400 MHz, MeOH- d₄): δ 8.86 (d, J= 5.48 Hz, 1H), 8.78 (s, 1H), 8.74 (d, J = 7.83 Hz, 1H), 7.86 (d, J =7.83 Hz, 1H), 7.69 (t, J = 7.83 Hz, 1H), 7.56 (d, J = 5.09 Hz, 1H), 4.78(s, 2H).

C12H12N2O2 217.0972 217.2 1.595/B ¹H NMR (400 MHz, MeOH- d₄): δ 8.74 (d,J = 5.09 Hz, 1H), 8.31-8.38 (m, 2H), 7.42 (d, J = 5.09 Hz, 1H), 6.98-7.05 (m, 2H), 4.72 (s, 2H), 3.87 (s, 3H).

Examples 98 to 100

The following additional Examples have been prepared, isolated andcharacterized according to the method disclosed in Example 97.

HPLC Retention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 98

C₂₈H₂₄N₆O₅S 557.1607 2.337/B 557.1598 ¹H NMR (400 MHz, DMSO- d₆): δ 8.98(d, J = 5.09 Hz, 1H), 8.43-8.49 (m, 2H), 8.40 (s, 1H), 7.69 (d, J = 5.09Hz, 1H), 7.54-7.60 (m, 2H), 7.15 (s, 1H), 6.85- 6.89 (m, 1H), 6.57 (d, J= 1.96 Hz, 1H), 5.46 (s, 2H), 4.21 (s, 3H), 3.79 (s, 3H), 3.01 (br s,3H), 2.94 (br s, 3H). 99

C₂₆H₁₈N₆O₄S 511.1189 2.517/B 511.1163 ¹H NMR (400 MHz, DMSO- d₆): δ 9.00(d, J = 5.09 Hz, 1H), 8.67-8.73 (m, 2H), 8.39 (s, 1H), 8.03 (d, J = 7.43Hz, 1H), 7.78 (t, J = 8.02 Hz, 1H), 7.74 (d, J = 5.09 Hz, 1H), 7.15 (s,1H), 6.87 (s, 1H), 6.57 (s, 1H), 5.48 (s, 2H), 4.21 (s, 3H), 3.79 (s,3H). 100

C₂₆H₂₁N₅O₅S 516.1342 2.550/B 516.1316 ¹H NMR (400 MHz, DMSO- d₆): δ 8.88(d, J = 5.09 Hz, 1H), 8.34-8.41 (m, 3H), 7.56 (d, J = 5.09 Hz, 1H), 7.13(s, 1H), 7.0-7.11 (m, 2H), 6.87 (s, 1H), 6.56 (s, 1H), 5.42 (s, 2H),4.21 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H).

Example 1012-Methoxy-6-(6-methoxy-4-((2-phenylpyrimidin-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

101A. Ethyl 2-phenylpyrimidine-4-carboxylate

To an ice-cold solution of benzimidamide hydrochloride (0.156 g, 0.996mmol) in ethanol (5 mL) was added dropwise a solution of lithium2-methylpropan-2-olate (1 M in THF, 1 mL, 1.00 mmol). The mixture wasstirred for 5 min and then (E)-ethyl 4-ethoxy-2-oxobut-3-enoate (0.223g, 1.295 mmol) was added. The mixture was then heated at 140° C.(microwave) for 20 min. The resulting dark mixture was concentrated onthe rotary evaporator and the residue was partitioned between ethylacetate (40 mL) and brine (20 mL). The aqueous layer was separated andre-extracted with ethyl acetate (2×20 mL) and the combined organicextract was washed with brine, dried (MgSO₄) and evaporated. Theobtained residue was purified on the ISCO using a REDISEP® Gold 12 gcolumn (elution with hexanes-EtOAc) to give the title compound (0.048 g,21%) as a solid. LC (Method F): 2.099 min. LCMS (APCI): calcd forC₁₃H₁₃N₂O₂ [M+H]⁺ m/z 229.097. found 229.2. ¹H NMR (400 MHz, CDCl₃): δ9.03 (d, J=5.1 Hz, 1H), 8.54 (dd, J=6.7, 3.1 Hz, 2H), 7.85 (d, J=5.1 Hz,1H), 7.47-7.57 (m, 3H), 4.53 (d, J=7.0 Hz, 2H), 1.49 (t, J=7.0 Hz, 3H).

101B: (2-Phenylpyrimidin-4-yl)methanol

An ice-cold solution of ethyl 2-phenylpyrimidine-4-carboxylate (0.048 g,0.210 mmol) in THF (3 mL) under nitrogen was treated with NaBH₄ (0.032g, 0.841 mmol) and methanol (0.051 mL, 1.262 mmol). The mixture wasstirred at 0° C. for 12 h, after which the mixture was allowed to stirat room temperature for 18 h. The resulting turbid solution wasre-cooled in an ice bath and quenched with saturated aqueous NH₄Cl (10mL) and diluted with ethyl acetate (40 mL). The aqueous layer wasseparated and re-extracted with ethyl acetate (2×20 mL). The combinedorganic extract was washed with saturated aqueous sodium bicarbonate(2×20 mL) and brine (20 mL) and then dried over anhydrous magnesiumsulfate. Evaporation of the solvent gave an oily residue that waspurified on the ISCO using a REDISEP® Gold 4 g column (elution withhexanes-EtOAc) to give the title compound (0.034 g, 87%) as an oil. LC(Method F): 1.688 min. LCMS (APCI): calcd for C₁₁H₁₁N₂O [M+H]⁺ m/z187.087. found 187.2. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (d, J=5.1 Hz, 1H),8.42-8.54 (m, 2H), 7.48-7.56 (m, 3H), 7.18 (d, J=5.1 Hz, 1H), 4.79-4.87(m, 2H), 3.62 (t, J=5.1 Hz, 1H).

Example 1012-Methoxy-6-(6-methoxy-4-((2-phenylpyrimidin-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.050 g, 0.158 mmol) and tri-n-butylphosphine (0.194 mL, 0.788 mmol)was pumped under high vacuum for 20 min. To this mixture was then added,at room temperature under nitrogen, a solution of(2-phenylpyrimidin-4-yl)methanol (0.0323 g, 0.173 mmol) in THF (4 mL),followed by the dropwise addition of a solution of1,1′-(azodicarbonyl)dipiperidine (0.099 g, 0.394 mmol) in THF (3 mL)over 20 min. The mixture was stirred at room temperature for anadditional 3 h and then it was diluted with dichloromethane (75 mL),washed twice with saturated aqueous NaHCO₃ (20 mL), water (20 mL) andbrine (20 mL), and finally dried (MgSO₄). Evaporation of the solventgave a semi-solid that was purified on the ISCO using a REDISEP® Gold 12g column (elution with hexanes-EtOAc) to give the slightly impureproduct. This material was repurified on the ISCO using a REDISEP® Gold12 g column (elution with dichloromethane-EtOAc) and the obtainedmaterial was further triturated with acetonitrile (1 mL) and theresulting solid was lyophilized from acetonitrile-water to give thetitle compound (0.046 g, 60.1%) as a solid. LC (Method F): 2.692 min.HRMS(ESI): calcd for C₂₅H₂₀N₅O₄S [M+H]⁺ m/z 486.1236. found 486.1217. ¹HNMR (400 MHz, CDCl₃): δ 8.95 (d, J=5.1 Hz, 1H), 8.41-8.46 (m, 2H), 8.40(s, 1H), 7.65 (d, J=5.1 Hz, 1H), 7.50-7.59 (m, 3H), 7.11-7.17 (m, 1H),6.87 (d, J=0.8 Hz, 1H), 6.57 (d, J=1.6 Hz, 1H), 5.45 (s, 2H), 4.21 (s,3H), 3.79 (s, 3H).

Preparation of Alcohols

The following additional intermediate alcohols were prepared accordingto the procedures described in Example 101.

Structure Calc. LCMS HPLC Retention (Employed in preparation of [M + H]⁺[M + H]⁺ Time (Min)/ Example as indicated) Formula m/z m/z Method NMR

C₉H₉N₃OS 208.0539 208.0 ¹H NMR (400 MHz, CDCl₃): δ 8.81 (d, J = 5.1 Hz,1H), 8.22 (s, 1H), 7.25 (s, 1H), 4.85 (d, J = 5.5 Hz, 2H), 3.22 (t, J =5.3 Hz, 1H), 2.85 (s, 3H).

C₈H₁₀N₂O 151.0866 151.2 0.889/F ¹H NMR (400 MHz, CDCl₃): δ 8.51 (d, J =5.1 Hz, 1H), 6.97-7.03 (m, 1 H), 4.69 (d, J = 5.1 Hz, 2H), 3.55 (t, J =5.1 Hz, 1H), 2.27 (tt, J = 7.9, 4.8 Hz, 1H), 1.14-1.21 (m, 2H), 1.07-1.14 (m, 2H).

C₁₃H₁₂N₂O₃ 245.0921 245.2 1.739/F ¹H NMR (400 MHz, CDCl₃): δ 8.77 (d, J= 5.1 Hz, 1 H), 7.32 (d, J = 5.1 Hz, 1 H), 7.05-7.12 (m, 1 H), 6.83-6.96(m, 3 H), 5.43 (dd, J = 6.8, 2.5 Hz, 1 H), 4.80 (d, J = 5.1 Hz, 2 H),4.63 (dd, J = 11.3, 2.3 Hz, 1 H), 4.48 (dd, J = 11.3, 7.0 Hz, 1 H), 3.08(t, J = 5.3 Hz, 1 H).

C₁₄H₁₄N₂O 227.1179 227.2 1.794/F ¹H NMR (400 MHz, CDCl₃): δ 8.51 (d, J =5.1 Hz, 1H), 7.40-7.47 (m, 2H), 7.33-7.40 (m, 2H), 7.28-7.33 (m, 1H),6.93 (d, J = 5.1 Hz, 1H), 4.63 (d, J = 4.7 Hz, 2H), 3.59 (t, J = 4.9 Hz,1H), 1.73-1.81 (m, 2H), 1.46 (q, J = 3.8 Hz, 2H).

Examples 102 to 105

The following additional Examples have been prepared, isolated andcharacterized according to the method disclosed in Example 101.

HPLC Retention Calc. Time LCMS [M + H]⁺ (Min)/ [M + H]⁺ Ex. StructureFormula m/z Method m/z NMR 102

C₂₃H₁₈N₆O₄S₂ 507.0904 507.0892 2.637/F ¹H NMR (400 MHz, DMSO- d₆): δ8.90 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 7.64 (d, J = 5.1Hz, 1H), 7.14 (s, 1H), 6.87 (d, J = 0.8 Hz, 1H), 6.55 (d, J = 2.0 Hz,1H), 5.41 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 2.75 (s, 3H). 103

C₂₂H₁₉N₅O₄S 450.1231 450.1218 2.585/F ¹H NMR (400 MHz, DMSO- d₆): δ 8.66(d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.09 (s,1H), 6.85 (dd, J = 1.8, 1.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.27 (s,2H), 4.21 (s, 3H), 3.79 (s, 3H), 2.15-2.26 (m, 1H), 0.95- 1.11 (m, 4H).104

C₂₇H₂₁N₅O₆S 544.1285 544.1312 2.643/F ¹H NMR (400 MHz, DMSO- d₆): δ 8.90(d, J = 5.5 Hz, 1H), 8.39 (s, 1H), 7.75 (d, J = 5.1 Hz, 1H), 7.12 (s,1H), 6.99 (dd, J = 7.8, 2.0 Hz, 1H), 6.80- 6.94 (m, 4H), 6.53 (d, J =2.0 Hz, 1H), 5.46 (dd, J = 6.7, 2.3 Hz, 1H), 5.39 (d, J = 2.7 Hz, 2H),4.62 (dd, J = 11.5, 2.5 Hz, 1H), 4.44 (dd, J = 11.7, 6.7 Hz, 1H), 4.21(s, 3H), 3.79 (s, 3H). 105

C₂₈H₂₃N₅O₄S 526.1544 526.1684 2.665/F ¹H NMR (400 MHz, DMSO- d₆): δ 8.63(d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.27- 7.39(m, 4H), 7.19-7.27 (m, 1H), 7.07 (s, 1H), 6.79- 6.88 (m, 1H), 6.47 (d, J= 2.0 Hz, 1H), 5.23 (s, 2H), 4.21 (s, 3H), 3.79 (s, 3H), 1.64 (q, J =3.4 Hz, 2H), 1.30-1.39 (m, 2H).

Example 106(2-(3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)-5-methylthiazol-4-yl)methanol

106A. (2-Bromo-5-methylthiazol-4-yl)methanol

A solution of methyl 2-bromo-5-methylthiazole-4-carboxylate (1.00 g,4.24 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C. under nitrogenand treated with methanol (0.343 mL, 8.47 mmol) followed by lithiumborohydride (0.185 g, 8.47 mmol), both added all at once. After 30 min,the cooling bath was removed and the resulting yellow solution wasstirred at room temperature for 1.5 h. The reaction mixture wasre-cooled at 0° C., quenched with acetic acid (6 drops) and water (1 mL)and vigorously stirred for 10 min. The resulting mixture was thendiluted with dichloromethane (200 mL), washed with saturated aqueoussodium bicarbonate and brine, and dried over anhydrous magnesiumsulfate. Concentration under reduced pressure afforded the titlecompound (0.83 g, 94%) as a white solid which was used as such in thenext step. HRMS(ESI): Calcd for C₅H₇BrNOS [M+H]⁺ m/z 207.9426. found207.9424. ¹H NMR (CDCl₃, 400 MHz): δ 4.63 (s, 2H), 2.42 (s, 3H), 2.30(br s, 1H).

106B. 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazole

In a 250 mL round-bottomed flask, a solution of crude(2-bromo-5-methylthiazol-4-yl)methanol (0.825 g, 3.96 mmol) in DMF (10mL) was maintained under vacuum (2 mbar) for 10 min. The flask was thenflushed with nitrogen and charged with imidazole (0.540 g, 7.93 mmol),followed by TBS-Cl (0.896 g, 5.95 mmol), both added in one portion. Theresulting clear solution was stirred at 23° C. for 18 h before the DMFwas evaporated under reduced pressure and the residue was partitionedwith ethyl acetate-saturated aqueous sodium bicarbonate. The organicphase was separated, washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The resulting oil was chromatographedon silica gel (3×12 cm, elution with toluene) to give the title compound(1.05 g, 82%) as a clear oil. LCMS (APCI): calcd for C₁₁H₂₁BrNOSSi[M+H]⁺ m/z 322.03. found 322.0. ¹H NMR (CDCl₃, 400 MHz): δ ppm 4.64 (s,2H), 2.34 (s, 3H), 0.81 (s, 9H), 0.00 (s, 6H).

106C.(3-(4-4(tert-Butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)phenyl)methanol

In a 75 mL glass pressure vial, a mixture of2-bromo-4-(((tert-butyldimethylsilyl)oxy)-methyl)-5-methylthiazole(0.400 g, 1.241 mmol), (3-(hydroxymethyl)phenyl)boronic acid (0.283 g,1.861 mmol) in toluene (14 mL) and EtOH (4 mL) was treated with 2 MNa₂CO₃ (0.745 mL, 1.489 mmol) and the resulting heterogeneous mixturewas flushed with nitrogen for 10 min. Then Pd(dppf)Cl₂.DCM (0.061 g,0.074 mmol) was added and the sealed vial was heated at 95° C. for 3 h.The cooled reaction mixture was partitioned between ethyl acetate (200mL) and saturated aqueous sodium bicarbonate (25 mL). The organic phasewas separated, washed with brine, dried over anhydrous magnesium sulfateand concentrated in vacuo. The brown syrup obtained was chromatographedon silica gel (gradient elution with toluene-ethyl acetate, 9:1 to 7:3)to give 0.365 g (84%) of the title compound as a white solid. LC (MethodB): 2.375 min. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.89 (br s, 1H), 7.78-7.82(m 1H), 7.37-7.45 (m, 2H), 4.85 (s, 2H), 4.76 (d, J=6.2 Hz, 2H), 2.53(s, 3H), 1.73 (t, J=6.2 Hz, 1H), 0.94 (s, 9H), 0.13 (s, 6H).

106D.6-(4-((3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

A mixture of6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.070 g, 0.221 mmol) and(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)phenyl)methanol(0.081 g, 0.232 mmol) in a 50 mL round-bottomed flask fitted with anaddition funnel was maintained under vacuum for 5 min. The flask wasthen flushed with nitrogen and charged with dry tetrahydrofuran (8 mL)and tri-n-butylphosphine (0.110 mL, 0.441 mmol), added in one portion.To this heterogeneous mixture was added a solution of(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (0.067 g, 0.265 mmol)in tetrahydrofuran (3 mL), drop-wise over 1 h. After stirring at roomtemperature for another 4 h, the reaction mixture was partitionedbetween ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate(20 mL). The organic phase was washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo to give a glassy lightyellow residue. This residue was chromatographed on silica gel (elutionwith toluene-ethyl acetate, 95:5 to 9:1) to give 0.116 g (66%) of thetitle compound as a white solid. LC (Method B): 2.829 min. ¹H NMR (400MHz, CDCl₃): δ ppm 7.97 (s, 1H), 7.85 (s, 1H), 7.84 (d, J=7.5 Hz, 1H),7.53 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.11 (s, 1H), 6.71 (brs, 1H), 6.41 (d, J=1.6 Hz, 1H), 5.23 (s, 2H), 4.86 (s, 2H), 4.21 (s,3H), 3.85 (s, 3H), 2.53 (s, 3H), 0.93 (s, 9H), 0.13 (s, 6H).

Example 106(2-(3-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)phenyl)-5-methylthiazol-4-yl)methanol

In a 100 mL round-bottomed flask, a solution of6-(4-((3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)benzyl)oxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.090 g, 0.139 mmol) in tetrahydrofuran (3 mL) was treated withtriethylamine trihydrofluoride (0.11 mL, 0.69 mmol), added all at once,and the resulting clear solution was stirred at 23° C. for 18 h. Thereaction was then quenched with saturated aqueous sodium bicarbonate (20mL) and dichloromethane (100 mL) and the mixture was stirred for 30 min.The aqueous phase was separated and back-extracted with dichloromethane(2×30 mL) and the combined organic phase was washed with brine, driedover anhydrous magnesium sulfate and concentrated in vacuo to give awhite solid. This material was crystallized from acetonitrile to give0.069 g (93%) of the title compound as a white solid. LC (Method B):2.456 min. HRMS(ESI): Calcd for C₂₆H₂₃N₄O₅S₂ [M+H]⁺ m/z 535.1104. found535.1114. ¹H NMR (400 MHZ, DMSO-d₆): δ ppm 8.40 (s, 1H), 8.02 (s, 1H),7.84 (br d, J=7.8 Hz, 1H), 7.58 (br d, J=7.8 Hz, 1H), 7.54 (t, J=7.8 Hz,1H), 7.02 (br d, 1H), 6.84-6.87 (m, 1H), 6.57 (d, J=2.0 Hz, 1H), 5.36(s, 2H), 5.13 (t, J=4.8 Hz, 1H), 4.55 (d, J=4.8 Hz, 2H), 4.22 (s, 3H),3.81 (s, 3H), 2.50 (s, 3H).

Example 1076-(6-Chloro-4-((3-(2-methoxypyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

107A. 4-Chloro-2,6-dimethoxybenzaldehyde

A solution of 1-chloro-3,5-dimethoxybenzene (5 g, 29.0 mmol) and TMEDA(4.37 mL, 29.0 mmol) in diethyl ether (100 mL, 962 mmol) at −78° C.under N₂ atmosphere was charged with BuLi (19.91 mL, 31.9 mmol) dropwiseover a period of 30 minutes using a syringe pump. After stirring for 4hours at −78° C., DMF was added and the reaction mixture continued tostir for 1.5 hours after which 1N HCl (˜30 mL) was added (all at −78°C.). The reaction mixture was warmed to room temperature and extractedwithy ethyl acetate. The organic phase was dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by ISCO usinghexanes/EtOAc as eluent. Fractions containing the desired product wereconcentrated to dryness to give the title material (1.97 g, 9.82 mmol,33.9% yield) as a light yellow solid. LC (Method B): 1.924 min. LCMS(APCI): calcd for C₉H₁₀ClO₃ [M+H]⁺ m/z 201.03. found 201.0. ¹H NMR(CDCl₃, 400 MHz): δ ppm 10.28 (s, 1H), 6.87 (s, 2H), 3.86 (s, 6H).

107B. 4-Chloro-2-hydroxy-6-methoxybenzaldehyde

A stirred solution of 4-chloro-2,6-dimethoxybenzaldehyde (1.95 g, 9.72mmol) in DCM (20 mL, 311 mmol) at −78° C. was slowly added borontribromide (9.72 mL, 9.72 mmol). The reaction mixture was stirred at−78° C. for 10 minutes then warmed to r.t. and stirred for 1 hour whilemonitoring reaction progress by LCMS. Once all s.m. had been consumed,the reaction was quenched with water and extracted with DCM. The organicphase was washed with brine, dried (MgSO₄), filtered and concentrated todryness to give the title material (1.79 g, 9.59 mmol, 99% yield) as apurple solid. LC (Method B): 2.199 min. LCMS (APCI): calcd for C₈H₈ClO₃[M+H]⁺ m/z 187.02. found 187.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 11.89 (s,1H), 10.20 (s, 1H), 6.75 (t, J=2.0 Hz, 1H), 6.66 (m, 1H), 3.91 (s, 1H).

107C. 1-(6-Chloro-4-methoxybenzofuran-2-yl)ethanone

A stirred solution of 4-chloro-2-hydroxy-6-methoxybenzaldehyde (1.79 g,9.59 mmol) in N,N-dimethylformamide (15 mL, 9.59 mmol) was charged withcesium carbonate (3.75 g, 11.51 mmol) and 1-chloropropan-2-one (0.975mL, 11.51 mmol). The reaction mixture was heated in a sealable vessel at65° C. for 7 hours, was filtered over a Whatman filter paper to removeinsolubles rinsing with DCM then washed with sat. NaHCO₃. The organicphase was dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by ISCO using hexanes/EtOAc as eluent. Fractionscontaining the desired product were concentrated to give the titlematerial (1.43 g, 6.37 mmol, 66% yield) as a light yellow solid. LC(Method A): 1.952 min. LCMS (APCI) calcd for C₁₁H₁₀ClO₃ [M+H]⁺ m/z225.03. found 225.0. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 7.94 (d, J=0.8 Hz,1H), 7.49 (dd, J=0.8, 1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 3.97 (s, 3H).

107D. 1-(6-Chloro-4-hydroxybenzofuran-2-yl)ethanone

To a stirred solution of 1-(6-chloro-4-methoxybenzofuran-2-yl)ethanone(1.43 g, 6.37 mmol) in chlorobenzene (15 mL, 148 mmol) was addedaluminum chloride (3.40 g, 25.5 mmol) in portions over a period of 10minutes. The reaction vessel was then sealed and heated at 100° C. for40 minutes, then cool to r.t. and poured onto crushed ice (rinsedstirring bar with EtOAc). This was stirred for 30 minutes, thenextracted with ethyl acetate. The organic phase was dried (MgSO₄),filtered and concentrated to dryness. The residue was purified by ISCOusing hexanes/EtOAc as eluent. Fractions containing the desired productwere concentrated to give the title material (1.18 g, 5.60 mmol, 88%yield) as a light brown solid. LC (Method A): 1.783 min. LCMS (APCI):calcd for C₁₀H₈ClO₃ [M+H]⁺ m/z 211.02. found 211.0. ¹H NMR (CDCl₃, 400MHz): δ ppm 11.01 (s, 1H), 7.89 (s, 1H), 6.72 (s, 1H), 2.52 (s, 3H).

107E. 1-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)ethanone

A stirred solution of 1-(6-chloro-4-hydroxybenzofuran-2-yl)ethanone(1.18 g, 5.60 mmol) in dry DMF (10 mL, 129 mmol) at r.t. was chargedwith K₂CO₃ (0.774 g, 5.60 mmol) and DMF. The reaction mixture wasstirred for 1.5 hours then partitioned between ethyl acetate and water.The organic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to dryness. The residue was purified by ISCO usinghexanes/EtOAc as eluent. Fractions containing the desired product wereconcentrated to give the title material (1.57 g, 5.22 mmol, 93% yield)as an amber colored oil. LC (Method B): 2.420 min. LCMS (APCI): calcdfor C₁₇H₁₄ClO₃ [M+H]⁺ m/z 301.06. found 301.0. ¹H NMR (CDCl₃, 400 MHz):δ ppm 8.00 (d, J=0.8 Hz, 1H), 7.53 (m, 3H), 7.44 (m, 2H), 7.38 (m, 1H),7.10 (d, J=1.6 Hz, 1H), 5.53 (s, 2H), 2.54 (s, 3H).

107F. 1-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone

A flame dried 200 ml round-bottom flask equipped with a stirring bar andunder nitrogen atmosphere was charged with anhydrous THF (12 mL)followed by lithium bis(trimethylsilyl)amide (6.22 mL, 6.22 mmol). Themixture was cooled to −78° C. and treated with a solution of1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)ethanone (1.56 g, 5.19 mmol) inTHF (6 ml+2 ml washing) added dropwise over 10 minutes via a syringepump. The resulting mixture was stirred at −78° C. for 45 minutes andwas then charged with trimethylchlorosilane (0.769 mL, 6.02 mmol) addeddropwise over 5 minutes by syringe pump then stirred for another 20minutes. The cooling bath was removed and the mixture was allowed towarm to +10° C. for 30 minutes. The reaction mixture was quenched with amixture of cold ethyl acetate (80 mL), sat. NaHCO₃ (12 mL) and ice. Theorganic phase was dried (MgSO₄), stirring for ˜5 minutes to remove alltraces of water), filtered and concentrated to dryness to give the silylenol ether as a yellow oil which was co-evaporated with toluene (4 mL).The silyl enol ether was dissolved in dry THF (20 mL), cooled to −30° C.(employing a cooling bath made from 1:1 CaCl₂: water using dry ice, bathstabilizes around −30 to −45° C.) and treated with NaHCO₃ (˜50 mgs)followed by N-bromosuccinimide (0.923 g, 5.19 mmol) added in smallportions over 15 minutes. The reaction mixture was allowed to warm to 0°C. over 2 hours (monitored by LCMS) and then quenched by addition ofethyl acetate (100 mL) and sat. NaHCO₃. The organic phase was washedwith brine, dried (MgSO₄) and evaporated to give an orange solid whichwas purified by ISCO using hexanes/EtOAc as eluent. Fractions containingthe desired product were concentrated to give the title material 1.48 g,3.51 mmol, 67.6% yield) as a yellow solid. LC (Method B): 2.528 min.LCMS (APCI): calcd for C₁₇H₁₃BrClO₃ [M+H]⁺ m/z 378.97. found 379.0.

107G.6-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole

A sealable vessel was charged with1-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoethanone (1.48 g, 3.51mmol), 5-bromo-1,3,4-thiadiazol-2-amine (0.632 g, 3.51 mmol) and IPA (25mL, 324 mmol). The reaction mixture was heated in an oil bath at 80° C.for 6 hours then heated in the microwave at 150° C. for 1 hour. Thereaction mixture was allowed to stand for 1 hour and the insolublematerial was filtered off and rinsed with MeOH to give the desiredproduct as a brown solid (1.19 g, 2.58 mmol, 73.6% yield). LC (MethodA): 2.549 min. LCMS (APCI): calcd for C₁₉H₁₂BrClN₃O₂S [M+H]⁺ m/z 459.95.found 460.0. ¹H NMR (CDCl₃, 400 MHz): δ ppm 8.74 (s, 1H), 7.55-7.50 (m,2H), 7.45-7.34 (m, 4H), 7.17 (d, J=0.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H),5.32 (s, 2H).

107H.6-(4-(Benzyloxy)-6-chlorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a stirred solution of6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole(1.18 g, 2.56 mmol) in DCM (40 mL, 622 mmol) and methanol (10 mL, 247mmol) was added sodium methoxide (1.164 mL, 5.12 mmol). The reactionmixture was stirred at r.t. for 1 h 15 min while monitoring by TLC (7:3hexanes: EtOAc). The reaction mixture was quenched with 1N HCl andextracted with DCM. The organic phase was washed with brine, dried(MgSO₄), filtered and concentrated to dryness. The residue wastriturated with MeOH (sonication) and the solid material was filteredoff, rinsed with MeOH and sucked dry to give the desired compound as abrown solid (859 mg, 2.086 mmol, 81% yield). LC (Method A): 2.478 min.LCMS (APCI): calcd for C₂₀H₁₅ClN₃O₃S [M+H]⁺ m/z 412.05. found 412.0. ¹HNMR (CDCl₃, 400 MHz) δ ppm: 8.50 (s, 1H), 7.52 (m, 2H), 7.43 (m, 2H),7.36 (m, 2H), 7.09 (d, J=0.8 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 5.31 (s,2H), 4.21 (s, 3H).

107I.6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

A stirred solution of6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.85 g, 2.064 mmol) and pentamethylbenzene (2.142 g, 14.45 mmol) in DCMunder N₂ atmosphere was cooled to −78° C. after which boron trichloride(5.16 mL, 5.16 mmol) was added dropwise over ˜4 minutes. The reactionwas monitored by TLC using 1:1 hexanes-EtOAc as eluent. The reactionmixture was stirred at −78° C. for 30 minutes after which a mixture ofwater (40 mL) and saturated NaHCO₃ (5 mL) was added (at −78° C.) and themixture was stirred until ambient temperature was obtained (removed fromcooling bath). The solid precipitate was filtered off and rinsed withdiethyl ether then allowed to dry overnight to give the title material(441 mgs, 1.371 mmol, 66.4% yield) as a beige solid. The filtrate wasextracted with DCM. The organic phase was washed with brine, dried(MgSO₄) and concentrated to dryness. The residue was purified by ISCOusing DCM/EtOAc as eluent. Fractions containing the desired product wereconcentrated to give the title material (25 mgs, 0.078 mmol, 3.77%yield) as a beige solid. LC (Method A): 2.167 min. LCMS (APCI): calcdfor C₁₃H₉ClN₃O₃S [M+H]⁺ m/z 322.00. found 322.0. ¹H NMR (CDCl₃, 400MHz): δ ppm 10.50 (br s, 1H), 8.45 (s, 1H), 7.17 (dd, J=0.8, 1.6 Hz,1H), 7.09 (d, J=0.8 Hz, 1H), 6.67 (d, J=2.0 Hz, 2H), 4.21 (s, 3H).

Example 1076-(6-Chloro-4-((3-(2-methoxypyrimidin-5-yl)benzyl)oxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried 100 mL round-bottomed flask containing6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(0.025 g, 0.078 mmol) and (3-(2-methoxypyrimidin-5-yl)phenyl)methanol(0.042 g, 0.194 mmol) in dry THF (4 mL) was added tri-n-butylphosphine(0.050 mL, 0.194 mmol). To this mixture was added a solution of ADDP(0.049 g, 0.194 mmol) in dry THF (1 mL) dropwise over 30 min (viasyringe pump). After stirring for 1.5 h at room temperature and thenheating to reflux for 2 h, tri-n-butylphosphine (0.050 mL, 0.194 mmol)and ADDP (0.049 g, 0.194 mmol) were again added and heating at refluxwas continued for 1.5 h. The cooled mixture was diluted with EtOAc, thenwashed with saturated aqueous NaHCO₃, water and brine. The organic phasewas dried (MgSO₄), then concentrated to dryness and the residue waspurified using the ISCO (gradient, 0 to 10% diethyl ether-DCM).Fractions containing the desired product were concentrated to give abeige solid which was further triturated with acetonitrile to give(after filtration and drying in vacuo) the title compound (0.026 g,64.4%) as a white solid. LC (Method A): 2.476 min. HRMS(ESI): calcd forC₂₅H₁₉ClN₅O₄S [M+H]⁺ m/z 520.0846. found 520.0865. ¹H NMR (DMSO-d₆, 400MHz): δ ppm 8.97 (s, 2H), 8.49 (s, 1H), 7.89 (br s, 1H), 7.73 (dt,J=2.3, 5.9 Hz, 1H), 7.59-7.54 (m, 2H), 7.39 (br s, 1H), 7.13 (d, J=0.8Hz, 1H), 7.05 (dd, J=0.4, 1.6 Hz, 1H), 5.37 (s, 2H), 4.20 (s, 3H), 3.98(s, 3H).

Example 1086-(6-Chloro-4-((3-(5-methoxypyrazin-2-yl)benzyl)oxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

The title compound was prepared according to the method described inExample 107 above. LC (Method A): 2.601 min. HRMS(ESI): calcd forC₂₅H₁₈ClN₅O₄S [M+H]⁺ m/z 520.0841. found 520.0845. ¹H NMR (DMSO-d₆, 400MHz): δ ppm 8.84 (d, J=1.2 Hz, 1H), 8.50 (s, 1H), 8.41 (d, J=1.6 Hz,1H), 8.18 (m, 1H), 8.01 (dt, J=1.8, 7.4 Hz, 1H), 7.60-7.54 (m, 2H), 7.38(dd, J=0.8, 1.6 Hz, 1H), 7.11 (d, J=0.8 Hz, 1H), 7.04 (d, J=1.6 Hz, 1H),5.39 (s, 2H), 4.21 (s, 3H), 3.97 (s, 3H).

Example 1094-(6-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo-furan-4-yl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

109A. 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

To a solution of (6-bromopyridin-2-yl)methanol (2.27 g, 12.07 mmol) andimidazole (2.466 g, 36.2 mmol) in DMF (50 mL) under N₂ was addedtert-butyldimethylchlorosilane (2.002 g, 13.28 mmol) and the resultingmixture was stirred at room temperature under N₂ for 18 h. The solutionwas then concentrated under reduced pressure and the residual oil waspartitioned with EtOAc—H₂O. The organic phase was separated, washed(H₂O, brine), dried (Na₂SO₄) and evaporated to give2-bromo-6-(((tert-butyldimethylsilyl)-oxy)methyl)pyridine (3.65 g, 100%)as a nearly colorless oil which was used as such in the next step. LC(Method A): 2.446 min. LCMS (APCI): calcd for C₁₂H₂₁BrNOSi [M+H]⁺ m/z302.058. found 302.1. ¹H NMR (400 MHz, CDCl₃): δ 7.45 (t, J=7.83 Hz,1H), 7.36 (d, J=7.83 Hz, 1H), 7.22 (d, J=7.83 Hz, 1H), 4.69 (s, 2H),0.84 (s, 9H), 0.00 (s, 6H).

109B.4-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

A solution of 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine(1.209 g, 4.000 mmol) in dry THF (7 mL) was cooled at −78° C. under N₂and then n-butyllithium (1.45 M in hexanes, 3.03 mL, 4.40 mmol) wasadded dropwise. The resulting mixture was stirred for 30 min to give abrown solution. To this mixture was slowly added a solution ofdihydro-2H-pyran-4(3H)-one (0.443 mL, 4.80 mmol) in dry THF (2 mL) andthe mixture was kept at −78° C. for 1 h to give a pale amber solution.The reaction was then quenched by the addition of saturated aqueousNH₄Cl (5 mL) and the mixture was partitioned with EtOAc-water. Theorganic phase was separated, the aqueous phase was back-extracted withEtOAc and the combined organic phase was washed (brine), dried (Na₂SO₄)and evaporated to give a pale yellow oil. Flash chromatography(Isco/0-40% EtOAc-hexane) afforded4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(0.728 g, 56.3%) as a colorless oil. LC (Method A): 2.084 min.HRMS(ESI): calcd for C₁₇H₃₀NO₃Si [M+H]⁺ m/z 324.1995. found 324.2076. ¹HNMR (400 MHz, DMSO-d₆): δ 7.72 (t, J=7.83 Hz, 1H), 7.45 (d, J=7.43 Hz,1H), 7.19 (d, J=7.43 Hz, 1H), 5.14 (s, 1H), 4.64 (s, 2H), 3.68-3.59 (m,4H), 2.07 (ddd, J=5.87, 11.74, 12.91 Hz, 2H), 1.32 (d, J=11.74 Hz, 1H),0.82 (s, 9H), 0.00 (s, 6H).

109C. 4-(6-(Hydroxymethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

To a solution of4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(Example XB, 0.403 g, 1.246 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (1.014 mL, 6.23 mmol) dropwise and themixture was stirred at room temperature for 16 h. The mixture was thendiluted with DCM and the solution was washed (saturated aqueous NaHCO₃),dried (Na₂SO₄) and evaporated to give4-(6-(hydroxymethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (0.199 g, 76%)as a colorless gum which solidified on standing. LC (Method A): 1.252min. HRMS(ESI): calcd for C₁₁H₁₆NO₃ [M+H]⁺ m/z 210.1130. found 210.1132.¹H NMR (400 MHz, DMSO-d₆): δ 7.75 (t, J=7.83 Hz, 1H), 7.48 (d, J=7.43Hz, 1H), 7.29 (d, J=7.43 Hz, 1H), 5.32 (t, J=5.87 Hz, 1H), 5.20 (s, 1H),4.51 (d, J=5.48 Hz, 2H), 3.75-3.66 (m, 4H), 2.13 (m, 2H), 1.38 (d,J=12.13 Hz, 2H).

Example 1094-(6-(((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.052 g, 0.165 mmol) and4-(6-(hydroxymethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (0.052 g,0.248 mmol), then the flask was flushed with N₂ and dry THF (3 mL) wasadded. To the resulting suspension was added tri-n-butylphosphine (0.107mL, 0.413 mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine(0.105 g, 0.413 mmol) in dry THF (2 mL) was added dropwise (via syringepump) over 30 min. The resulting mixture was stirred at room temperaturefor another 30 min and then it was diluted with EtOAc, washed (saturatedaqueous NaHCO₃, H₂O, brine), dried (Na₂SO₄) and evaporated to give apale yellow solid. This material was triturated with a minimum volume ofDCM and the resulting suspension was filtered and the filter-cake waswashed with DCM, then MeOH and finally DCM. The filter-cake was dried invacuo to give pure4-(6-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)-methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(0.055 g, 65.5%) as a cream solid. LC (Method A): 2.241 min. HRMS(ESI):calcd. for C₂₅H₂₅N₄O₆S [M+H]⁺ m/z 509.1495. found 509.1517. ¹H NMR (400MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.83 (t, J=7.83 Hz, 1H), 7.60 (d, J=7.83Hz, 1H), 7.43 (d, J=7.83 Hz, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.51 (d,J=1.57 Hz, 1H), 5.28 (s, 2H), 5.26 (s, 1H), 4.17 (s, 3H), 3.76-3.69 (m,4H), 3.75 (s, 3H), 2.19 (m, 2H), 1.43 (d, J=12.91 Hz, 2H).

Example 110(S)-4-(6-(((2-(2-(1-Fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 64C, 0.045 g, 0.135 mmol) and4-(6-(hydroxymethyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (Example 109C,0.034 g, 0.162 mmol), then the flask was flushed with N₂ and dry THF (3mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.088 mL, 0.337 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.086 g, 0.337 mmol) in dry THF (2 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 1 h and then it was dilutedwith EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried(Na₂SO₄) and evaporated to give a yellow gum. Flash chromatography(Isco/0-40% ether-DCM) gave(S)-4-(6-(((2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thia-diazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)-methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(0.060 g, 85%) as a cream solid. LC (Method A): 2.283 min. HRMS(ESI):calcd for C₂₆H₂₆FN₄O₅S [M+H]⁺ m/z 525.1608. found 525.1646. ¹H NMR (400MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.83 (t, J=7.83 Hz, 1H), 7.60 (d, J=7.83Hz, 1H), 7.44 (d, J=7.83 Hz, 1H), 7.10 (s, 1H), 6.81 (s, 1H), 6.52 (d,J=1.96 Hz, 1H), 6.13 (dq, J=6.26, 46.95 Hz, 1H), 5.29 (s, 2H), 5.23 (s,1H), 3.76 (s, 3H), 3.71 (m, 4H), 3.75 (s, 3H), 2.20 (m, 2H), 1.76 (dd,J=6.26, 24.65 Hz, 3H), 1.43 (d, J=12.52 Hz, 2H).

Example 1112-Methoxy-6-(6-methoxy-4-((6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

111A.2-4(tert-Butyldimethylsilyl)oxy)methyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridine

To a suspension of sodium hydride (0.047 g, 1.168 mmol) [Note: 60% NaHin oil was washed free of oil with hexane (×2) before dry THF was addedto the reaction flask] in dry THF (1 mL) under N₂ was added a solutionof4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(Example 109B, 0.189 g, 0.584 mmol) in dry THF (4 mL) and the mixturewas stirred at room temperature for 30 min to give a light yellow turbidmixture, with no more gas evolution being observed. To the resultingmixture was added iodomethane (0.044 mL, 0.701 mmol) dropwise andstirring was continued at room temperature for 18 h. The reactionmixture was then quenched by the careful addition of saturated aqueousNH₄Cl (5 mL) and the mixture was partitioned with EtOAc-water. Theorganic phase was separated, dried (Na₂SO₄) and evaporated to give apale yellow gum. Flash chromatography (Isco/0-50% EtOAc-hexane) afforded2-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridine(0.175 g, 89%) as a colorless oil which was used as such in the nextstep. LC (Method A): 2.397 min. HRMS(ESI): calcd for C₁₈H₃₂NO₃Si [M+H]⁺m/z 338.2151. found: 338.2205. ¹H NMR (400 MHz, DMSO-d₆): δ 7.76 (t,J=7.83 Hz, 1H), 7.29 (d, J=7.83 Hz, 1H), 7.25 (d, J=7.83 Hz, 1H), 4.65(s, 2H), 3.57 (dd, J=2.74, 8.22 Hz, 4H), 2.85 (s, 3H), 2.05 (dt, J=8.22,13.69 Hz, 4H), 1.79 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

111B. (6-(4-Methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanol

To a solution of2-4(tert-butyldimethylsilyl)oxy)methyl)-6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridine(0.171 g, 0.507 mmol) in dry THF (10 mL) under N₂ was addedtriethylamine trihydrofluoride (0.412 mL, 2.53 mmol) dropwise and themixture was stirred at room temperature for 16 h. The mixture was thendiluted with DCM and the solution was washed (saturated aqueous NaHCO₃),dried (Na₂SO₄) and evaporated to give(6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanol (0.112 g,99%) as a colorless gum which crystallized on standing. This materialwas essentially pure and was used as such in the next step. LC (MethodA): 0.869 min. HRMS(ESI): calcd for C₁₂H₁₆NO₃ [M+H]⁺ m/z 224.1287. found224.1304. ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (t, J=7.83 Hz, 1H), 7.34 (d,J=7.83 Hz, 1H), 7.32 (d, J=7.83 Hz, 1H), 5.33 (t, J=5.48 Hz, 1H), 4.52(d, J=5.48 Hz, 2H), 3.64 (m, 4H), 2.93 (s, 3H), 2.05 (m, 2H), 1.79 (m,2H).

Example 1112-Methoxy-6-(6-methoxy-4-((6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried flask was added6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol(Example 1G, 0.048 g, 0.150 mmol) and(6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanol (0.042 g,0.188 mmol), then the flask was flushed with N₂ and dry THF (2 mL) wasadded. To the resulting suspension was added tri-n-butylphosphine (0.097mL, 0.375 mmol) and then a solution of 1,1′-(azodicarbonyl)dipiperidine(0.096 g, 0.375 mmol) in dry THF (2 mL) was added dropwise (via syringepump) over 30 min. The resulting mixture was stirred at room temperaturefor 1 h to give a slurry which was diluted with EtOAc, washed (saturatedaqueous NaHCO₃), dried (Na₂SO₄) and evaporated to give a solid residue.This material was taken up in DCM-MeOH and the solution was loaded on asilica gel pre-column, which was subsequently dried with a flow of air.Flash chromatography (Isco/0-30% ether-DCM) afforded2-methoxy-6-(6-methoxy-4-((6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.077 g, 98%) as a pale yellow gum. This material was lyophilized fromMeCN-water to give a white solid. LC (Method A): 2.376 min. HRMS(ESI):calcd for C₂₆H₂₇N₄O₆S [M+H]⁺ m/z 523.1651. found 523.1672. ¹H NMR (400MHz, DMSO-d₆): δ 8.34 (s, 1H), 7.87 (t, J=7.43 Hz, 1H), 7.49 (d, J=7.43Hz, 1H), 7.44 (d, J=7.83 Hz, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.51 (d,J=1.96 Hz, 1H), 5.29 (s, 2H), 4.17 (s, 3H), 3.75 (s, 3H), 3.65 (dd,J=2.35, 7.83 Hz, 4H), 2.94 (s, 3H), 2.09 (dt, J=7.83, 14.09 Hz, 2H),1.84 (d, J=12.91 Hz, 2H).

Example 112(S)-2-(1-Fluoroethyl)-6-(6-methoxy-4-((6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To a flame-dried flask was added(S)-2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-ol(Example 64C, 0.050 g, 0.150 mmol) and(6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanol (Example 111B, 0.042 g, 0.188 mmol), then the flask was flushed with N₂ and dry THF(2 mL) was added. To the resulting suspension was addedtri-n-butylphosphine (0.097 mL, 0.375 mmol) and then a solution of1,1′-(azodicarbonyl)dipiperidine (0.096 g, 0.375 mmol) in dry THF (2 mL)was added dropwise (via syringe pump) over 30 min. The resulting mixturewas stirred at room temperature for another 30 min and then it wasdiluted with EtOAc, washed (saturated aqueous NaHCO₃, H₂O, brine), dried(Na₂SO₄) and evaporated to give a light yellow gum. Flash chromatography(Isco/0-30% ether-DCM) afforded(S)-2-(1-fluoroethyl)-6-(6-methoxy-4-((6-(4-methoxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)benzofuran-2-yl)imidazo-[2,1-b][1,3,4]thiadiazole(0.074 g, 92%) as pale yellow gum. This material was lyophilized fromMeCN-water as an off-white solid. LC (Method A): 2.395 min. HRMS(ESI):calcd for C₂₇H₂₈FN₄O₅S [M+H]⁺ m/z 539.1764. found 539.1787. ¹H NMR (400MHz, DMSO-d₆): δ 8.55 (s, 1H), 7.84 (t, J=7.83 Hz, 1H), 7.47 (d, J=7.83Hz, 1H), 7.41 (d, J=7.83 Hz, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 6.49 (d,J=1.96 Hz, 1H), 6.10 (dq, J=6.65, 46.95 Hz, 1H), 5.27 (s, 2H), 3.72 (s,3H), 3.62 (dd, J=2.74, 7.83 Hz, 4H), 2.91 (s, 3H), 2.06 (dt, J=7.43,14.09 Hz, 2H), 1.81 (d, J=12.13 Hz, 2H), 1.73 (dd, J=6.65, 24.65 Hz,3H).

Example 1136-(4-((6-(4-Fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold mixture of4-(6-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(Example 109, 0.015 g, 0.029 mmol) in DCM (2 mL) under N₂ was added DAST(4.87 μL, 0.037 mmol) dropwise and the resulting mixture was stirred at0° C. for 1 h. Another aliquot of DAST (9.45 μl, 0.071 mmol) was addedand stirring was continued at 0° C. for another 1 h. The cooling bathwas removed and after 30 min another aliquot of DAST (9.45 μl, 0.071mmol) was added and stirring was continued at room temperature for 1 h.The reaction mixture was then re-cooled at 0° C. and quenched by thedropwise addition of saturated aqueous NaHCO₃ (1 mL). The mixture wasvigorously stirred at 0° C. for 5 min and then the cooling bath wasremoved, the mixture was diluted with DCM-saturated aqueous NaHCO₃ andstirring was continued until no more gas evolution was observed. Theorganic phase was then separated, dried (Na₂SO₄) and evaporated to givea pale yellow gum. Flash chromatography (Isco/0-100% EtOAc-hexane)afforded6-(4-((6-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)-6-methoxy-benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole(0.009 g, 59.8%) as a colorless gum which was lyophilized fromMeCN-water to give a white solid. LC (Method A): 2.421 min. HRMS(ESI):calcd for C₂₅H₂₄FN₄O₅S [M+H]⁺ m/z 511.1451. found 511.1468. ¹H NMR (400MHz, DMSO-d₆): δ 8.32 (s, 1H), 7.89 (t, J=7.83 Hz, 1H), 7.52 (d, J=7.83Hz, 1H), 7.49 (d, J=7.83 Hz, 1H), 6.97 (s, 1H), 6.77 (s, 1H), 6.48 (d,J=1.96 Hz, 1H), 5.27 (s, 2H), 4.14 (s, 3H), 3.81 (dd, J=5.89, 11.74 Hz,2H), 3.72 (s, 3H), 3.63 (t, J=11.74 Hz, 2H), 2.32-2.14 (m, 2H), 1.78 (t,J=13.30 Hz, 2H).

Example 114(S)-2-(1-Fluoroethyl)-6-(4-((6-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)-6-methoxybenzo-furan-2-yl)imidazo[2,1-b][1,3,4]thiadiazole

To an ice-cold mixture of(S)-4-(6-(((2-(2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-ol(Example 110, 0.015 g, 0.029 mmol) in DCM (2 mL) under N₂ was added DAST(9.45 μL, 0.072 mmol) dropwise and the resulting mixture was stirred at0° C. to room temperature for 1.5 h. Another aliquot of DAST (4.73 μL,0.036 mmol) was then added and stirring was continued at roomtemperature for another 30 min. The reaction mixture was then re-cooledat 0° C. and quenched by the dropwise addition of saturated aqueousNaHCO₃ (1 mL). The mixture was vigorously stirred at 0° C. for 5 min,then the cooling bath was removed, the mixture was diluted with DCM,saturated aqueous NaHCO₃ was added and stirring was continued until nomore gas evolution was observed. The organic phase was separated, dried(Na₂SO₄) and evaporated to give a pale yellow gum. Flash chromatography(Isco/0-100% EtOAc-hexane) gave(S)-2-(1-fluoroethyl)-6-(4-((6-(4-fluorotetrahydro-2H-pyran-4-yl)pyridin-2-yl)methoxy)-6-methoxy-benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole(0.011 g, 73.0%) as an off-white solid. LC (Method A): 2.433 min.HRMS(ESI): calcd for C₂₆H₂₅F₂N₄O₄S [M+H]⁺ m/z 527.1565. found 527.1590.¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (s, 1H), 7.89 (t, J=7.83 Hz, 1H), 7.53(d, J=7.83 Hz, 1H), 7.48 (d, J=7.83 Hz, 1H), 7.08 (s, 1H), 6.79 (s, 1H),6.50 (d, J=1.57 Hz, 1H), 6.10 (dq, J=6.26, 46.95 Hz, 1H), 5.28 (s, 2H),3.81 (dd, J=6.26, 11.74 Hz, 2H), 3.73 (s, 3H), 3.63 (t, J=11.74 Hz, 2H),2.33-2.15 (m, 2H), 1.78 (m, 2H), 1.73 (dd, J=6.26, 24.65 Hz, 3H).

Biology

The term “PAR4 antagonist” denotes an inhibitor of platelet aggregationwhich binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically,PAR4 activity is reduced in a dose dependent manner by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to suchactivity in a control cell. The control cell is a cell that has not beentreated with the compound. PAR4 activity is determined by any standardmethod in the art, including those described herein (for example calciummobilization in PAR4 expressing cells, platelet aggregation, plateletactivation assays measuring e.g., calcium mobilization, p-selectin orCD40L release, or thrombosis and hemostasis models). The term “PAR4antagonist” also includes a compound that inhibits both PAR1 and PAR4.

It is desirable to find compounds with advantageous and improvedcharacteristics compared with known anti-platelet agents, in one or moreof the following categories that are given as examples, and are notintended to be limiting: (a) pharmacokinetic properties, including oralbioavailability, half life, and clearance; (b) pharmaceuticalproperties; (c) dosage requirements; (d) factors that decrease bloodconcentration peak-to-trough characteristics; (e) factors that increasethe concentration of active drug at the receptor; (f) factors thatdecrease the liability for clinical drug-drug interactions; (g) factorsthat decrease the potential for adverse side-effects, includingselectivity versus other biological targets; (h) improved therapeuticindex with less propensity for bleeding; and (h) factors that improvemanufacturing costs or feasibility.

The term “compound”, as used herein, means a chemical, be itnaturally-occurring or artificially-derived. Compounds may include, forexample, peptides, polypeptides, synthetic organic molecules, naturallyoccurring organic molecules, nucleic acid molecules, peptide nucleicacid molecules, and components and derivatives thereof.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or nonhumanorganism that could potentially benefit from treatment with a PAR4antagonist. Exemplary subjects include human beings of any age with riskfactors for cardiovascular disease, or patients that have alreadyexperienced one episode of cardiovascular disease. Common risk factorsinclude, but are not limited to, age, male sex, hypertension, smoking orsmoking history, elevation of triglycerides, elevation of totalcholesterol or LDL cholesterol.

In some embodiments, the subject is a species having a dual PAR1/PAR4platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4platelet receptor repertoire” means that a subject expresses PAR1 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR1/PAR4 platelet receptor repertoire include human beings, non-humanprimates, and guinea pigs.

In other embodiments, the subject is a species having a dual PAR3/PAR4platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4platelet receptor repertoire” means that a subject expresses PAR3 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR3/PAR4 platelet receptor repertoire include rodents and rabbits.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting its development; and/or(b) relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit and/or antagonize PAR4 and/or toprevent or treat the disorders listed herein. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi) within a blood vessel that may causeischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population. (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005).) Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular weight heparin preparations have been approvedby the FDA for these indications.

The term “pharmaceutical composition”, as used herein, means anycomposition, which contains at least one therapeutically or biologicallyactive agent and is suitable for administration to the patient. Any ofthese formulations can be prepared by well-known and accepted methods ofthe art. See, for example, Gennaro, A. R., ed., Remington: The Scienceand Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa.(2000).

The invention includes administering to a subject a pharmaceuticalcomposition that includes a compound that binds to PAR4 and inhibitsPAR4 cleavage and/or signaling (referred to herein as a “PAR4antagonist” or “therapeutic compound”).

The compounds of this disclosure can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The preferred dose of the PAR4 antagonist is a biologically active dose.A biologically active dose is a dose that will inhibit cleavage and/orsignaling of PAR4 and have an anti-thrombotic effect. Desirably, thePAR4 antagonist has the ability to reduce the activity of PAR4 by atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or morethan 100% below untreated control levels. The levels of PAR4 inplatelets is measured by any method known in the art, including, forexample, receptor binding assay, platelet aggregation, plateletactivation assays (e.g., p-selectin expression by FACS), Western blot orELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively,the biological activity of PAR4 is measured by assessing cellularsignaling elicited by PAR4 (e.g., calcium mobilization or other secondmessenger assays).

In some embodiments, a therapeutically effective amount of a PAR4compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferredembodiment, the therapeutically effective amount of the PAR4 compound isless than 5 mg/kg. In a most preferred embodiment, the therapeuticallyeffective amount of the PAR4 compound is less than 1 mg/kg. Effectivedoses vary, as recognized by those skilled in the art, depending onroute of administration and excipient usage.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfate, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Dispersion

A spray dried dispersion can be prepared for oral administration bymethods know to one skilled in the art.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, IAA, IA, IB, IC, ID, IE,IF, IG, IH, IJ, IK, IL, IM, IP or IQ, preferably, a compound selectedfrom one of the examples, more preferably a compound selected fromExamples 3 to 114, generally the amount of each component in a typicaldaily dosage and typical dosage form may be reduced relative to theusual dosage of the agent when administered alone, in view of theadditive or synergistic effect of the therapeutic agents whenadministered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the examples and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Additionally, certain compounds disclosed herein may be useful asmetabolites of other compounds. Therefore, in one embodiment, compoundsmay be useful either as a substantially pure compound, which may alsothen be incorporated into a pharmaceutical composition, or may be usefulas metabolite which is generated after administration of the prodrug ofthat compound. In one embodiment, a compound may be useful as ametabolite by being useful for treating disorders as described herein.

The activity of the PAR4 antagonists of the present invention can bemeasured in a variety of in vitro assays. Exemplary assays are shown inthe Examples below.

The FLIPR assay is an exemplary in vitro assay for measuring theactivity of the PAR4 antagonists of the present invention. In thisassay, intracellular calcium mobilization is induced in PAR4 expressingcells by a PAR4 agonist and calcium mobilization is monitored. See,e.g., Example A.

AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist isH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. As shown in ExampleB below, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ wasvalidated as a PAR4 agonist in the FLIPR assay. A side-by-sidecomparison of the IC₅₀ values of ˜180 compounds were performed usingAYPGKF versus H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. Theresults demonstrated a strong correlation between the two assays.Additionally, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ hasimproved agonist activity as compared to AYPGKF with an EC₅₀ that is 10fold lower than the EC₅₀ for AYPGKF in the FLIPR assay.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ can be synthesizedusing methods well known to those of skill in the art.

The FLIPR assay can also be used as a counterscreen to test agonistactivity or PAR1 antagonist activity in a cell line that expresses bothPAR1 and PAR4. The PAR1 antagonist activity can be tested by the abilityof the compound to inhibit calcium mobilization induced by the PAR1agonist peptide SFLLRN or other PAR1 agonist peptides.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by gamma-thrombin asshown in Example C. Gamma-thrombin, a proteolytic product ofalpha-thrombin which no longer interacts with PAR1, selectively cleavesand activates PAR4 (Soslau, G. et al., “Unique pathway ofthrombin-induced platelet aggregation mediated by glycoprotein Ib”, J.Biol. Chem., 276:21173-21183 (2001)). Platelet aggregation can bemonitored in a 96-well microplate aggregation assay format or usingstandard platelet aggregometer. The aggregation assay can also beemployed to test the selectivity of the compound for inhibiting plateletaggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP,or thromboxane analogue U46619.

Example D is an alpha-thrombin-induced platelet aggregation assay.Alpha-thrombin activates both PAR1 and PAR4. The ability of a selectivePAR4 antagonist of the present invention, Example 13, to inhibitplatelet aggregation was measured using a standard optical aggregometer.Inhibition of alpha-thrombin induced platelet aggregation by Example 13is shown in FIGS. 1 and 2. The data shows that a PAR4 antagonist alonecan effectively inhibit platelet aggregation. The extent of plateletinhibition by the PAR4 antagonist is at least comparable to what hasbeen previously described for PAR1 antagonists.

Example E is a tissue factor-induced platelet aggregation assay. Theconditions in this assay mimic the physiological events during thrombusformation. In this assay, platelet aggregation in human PRP wasinitiated by the addition of tissue factor and CaCl₂. Tissue factor, theinitiator of the extrinsic coagulation cascade, is highly elevated inhuman atherosclerotic plaque. Exposure of blood to tissue factor at theatherosclerotic site triggers a robust generation of thrombin andinduces the formation of obstructive thrombi.

FIGS. 1 and 2 show effective inhibition of tissue factor-inducedplatelet aggregation by the compound of Example 13 (a PAR4 antagonist ofthe present invention), as well as bytrans-cinnamoyl-Phe(4-F)-Phe(4-guanidino)-Leu-Arg-Arg-NH₂ (a PAR1antagonist). The PAR4 antagonist, like the PAR1 antagonist, is shown toeffectively inhibit tissue factor induced platelet aggregation in thisassay. This data demonstrates that the PAR4 antagonists of the presentinvention can effectively inhibit thrombin mediated platelet aggregationand can serve as antithrombotic agents. Thus, PAR4 antagonists representa novel class of antithrombotic agents that prevent robust plateletactivation by thrombin during thrombotic events.

The efficacy of the PAR4 antagonists of the present invention inpreventing thrombosis can also be measured in a variety of in vivoassays. Exemplary mammals that can provide models of thrombosis andhemostasis to test the effectiveness of the PAR4 antagonists of thepresent invention as antithrombotic agents include, but are not limitedto, guinea pigs and primates. Relevant efficacy models include, but arenot limited to, electrolytic injury-induced carotid artery thrombosis,FeCl₃-induced carotid artery thrombosis and arteriovenous-shuntthrombosis. Models of kidney bleeding time, renal bleeding time andother bleeding time measurements can be used to assess the bleeding riskof the antithrombotic agents described in the current invention. ExampleG describes an in vivo model of arterial thrombosis in cynolmolgusmonkeys. Compounds of the present invention can be tested in this modelfor their ability to inhibit thrombus formation induced by electrolyticinjury of the carotid artery. Demonstration of efficacy in this modelsupports the utility of PAR4 antagonists of the present invention fortreatment of thromboembolic diseases.

Assays Materials 1) PAR1 and PAR4 Agonist Peptides

SFFLRR is a known high affinity PAR1 selective agonist peptide.(Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars inThrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonistpeptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay(EC₅₀ of 8 μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and60 μM for AYPGKF) and in washed platelet aggregation assay (EC₅₀ of 0.9μM for H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 12 μM forAYPGKF).

2) PAR4 Expressing Cells

HEK293 cells stably expressing PAR4 were generated by a standard methodof transfection of human F2R23 cDNA expression vector or by RAGEtechnology from Athersys Inc. (Cleveland, Ohio) and selected based onPAR4 protein expression of mRNA expression. Those cells demonstratedfunctional responses to PAR4 agonist peptide-induced intracellularcalcium elevation using FLIPR® (Fluorometric Imaging Plate Reader;Molecular Devices Corp.). These cells express endogenous PAR1 and canelicit calcium signal upon stimulation with PAR1 agonist peptide. Cellswere grown in Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen,Carlsbad, Calif.), 10% FBS, 1% PSG, 3 μg/ml puromycin and 25 nMMethotrexate) at 37° C. with 5% CO₂.

3) Preparation of Platelet Rich Plasma (PRP)

Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per9 ml blood. The platelet rich plasma was isolated by centrifugation at170 g for 14 minutes.

4) Preparation of Washed Platelets (WP)

Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citricacid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.PRP was isolated by centrifugation at 170 g for 14 minutes and plateletswere further pelleted by centrifugation at 1300 g for 6 minutes.Platelets were washed once with 10 ml ACD containing 1 mg/ml bovineserum albumin. Platelets were resuspended at ˜2.5×10⁸/ml in Tyrode'sBuffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose,20 mM HEPES pH 7.4).

Example A FLIPR Assay in PAR4-Expressing HEK293 Cells

The activity of the PAR4 antagonists of the present invention weretested in PAR4 expressing cells by monitoringH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂-induced intracellularcalcium mobilization using FDSS6000 (Hamamatsu Photonics, Japan) byfluo-4. Counter screens for agonist activity and PAR1 antagonistactivity were also performed. Briefly, HEK293 EBNA PAR4 clone 20664.1Jcells were plated 24 hrs. prior to experiment in 384 well, Poly-D-Lysinecoated, black, clear bottom plates (Greiner Bio-One, Monroe, N.C.).Cells were plated at 20,000 cells/well in 20 μl growth medium andincubated at 37° C. with 5% CO₂ overnight. At time of assay, media wasreplaced with 40 μl 1×Hank's Buffered Saline Solution (HBSS) (with 10 mMHEPES) and 20 μl test compound also diluted in 1×HBSS buffer was addedat various concentrations and 0.67% DMSO final concentration on the FDSSfor agonist measurement. The cells were then incubated for 30 minutes atroom temperature followed by addition of 20 μl of agonist peptide forantagonist measurement on the FDSS. The agonist peptideH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ for PAR4 antagonistscreen or SFFLRR for PAR1 counter screen were routinely tested to ensurea response at EC₅₀ in the assay (˜2.5 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 600 nM forSFFLRR).

Example B Validation ofH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ as a PAR4 Agonist

To validate H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ as a PAR4agonist in the FLIPR assay, side-by-side comparison of the IC₅₀ valuesof −180 compounds were performed using AYPGKF versusH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. The resultsdemonstrated a strong correlation between the two assays (Spearman'srank correlation coefficient rho=0.7760, p<0.0001). The relevance of theFLIPR assay in the HEK293 cells was confirmed by a direct assayconnectivity to the washed platelet assay. The IC₅₀ values of ˜200compounds from AYPGKF FLIPR assay was strongly correlated to that fromAYPGKF washed platelet aggregation assay (Spearman's rank correlationcoefficient rho=0.836, p<0.001). Similar results were obtained comparingFLIPR and washed platelet data usingH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂.

Example C Gamma Thrombin Induced Platelet Aggregation Assays

The ability of the compounds of the current invention to inhibitplatelet aggregation induced by gamma-thrombin was tested in a 96-wellmicroplate aggregation assay format. Briefly, PRP or washed plateletsuspension (100 μl) was pre-incubated for 5 minutes at room temperaturewith varying concentrations of compounds. Aggregation was initiated by˜10-50 nM gamma thrombin (Haematologic Technologies, Essex Junction,Vt.), which was titrated daily to achieve 80% platelet aggregation.Refludan at 1 U/mL (Berlex, Montville, N.J.) was added to the gammathrombin sample to prevent PAR1 activation induced by residualalpha-thrombin contamination. The plate was then placed into a 37° C.Molecular Devices (Sunnyvale, Calif.) SPECTRAMAX® Plus Plate Reader. Theplate was mixed for 10 seconds before the first read and 50 secondsbetween each read for up to 15 minutes at 405 nM. Data was collectedwith SOFTMAX® 4.71 software. The plate also included an untreatedcontrol sample which served as ODmax, while buffer containing noplatelets was the ODmin. Platelet aggregation was determined bysubtracting the ODmax from the ODmin for the 100% aggregation value. Inexperimental samples, the observed transmission was subtracted from theminimum value and then compared to the 100% aggregation value todetermine the percentage aggregation. IC₅₀ values are determined usingExcel Fit software.

The aggregation assays were also employed to test the selectivity of thecompound against other platelet receptors by using SFFLRR for PAR1,collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP forP2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) forthromboxane receptors.

Example D Alpha-Thrombin Induced Platelet Aggregation Assays

The ability of a PAR4 antagonist (Example 13) compound to inhibitplatelet aggregation induced by alpha-thrombin was tested using humanwashed platelets. Example 13 was pre-incubated with washed platelets for20 min. Aggregation was initiated by addition of 1.5 nM alpha-thrombin(Haematologic Technologies, Essex Junction, Vt.) to 300 μl of washedplatelets at stirring speed of 1000 rpm. Platelet aggregation wasmonitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) andthe area under the curve (AUC) at 6 min was measured. IC₅₀ wascalculated using vehicle control as 0% inhibition. FIG. 1 shows %aggregation over time of human washed platelets induced by 1.5 nMalpha-thrombin employing the Example 13 compound in amounts of 0 nM, 3nM, 100 nM and 300 nM. The IC₅₀ for the inhibition of plateletaggregation by Example 13 using 1.5 nM alpha-thrombin was calculated tobe 11 nM (FIG. 2).

Example E Tissue Factor-Induced Platelet Aggregation Assay

The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregationinduced by endogenous thrombin can be tested in a tissue factor drivenaggregation assay. Aggregation is initiated by addition of CaCl₂ andrecombinant human tissue factor, which results in the generation ofthrombin through activation of the coagulation pathway in the plasma.Anticoagulant agents such as corn trypsin inhibitor (HaematologicTechnologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG(Centerchem, Norwalk, Conn.) are also added to the sample to preventfibrin clot formation during the time of the study. Platelet aggregationis monitored using standard instrumentation including opticalaggregometer or impedance aggregometer.

Example F

The following table sets out the results obtained employing variouscompounds of the invention tested in the FLIPR and platelet aggregationassay (PRP assay). As indicated above, the FLIPR assay, an in vitroassay, measures the PAR4 antagonist activity of compounds tested asdescribed in Example A. The γ-thrombin induced platelet aggregationassay in PRP, measures the PAR4 antagonist activity of the compoundstested as described in Example C.

TABLE 1 Example No. PAR4 FLIPR Assay (IC₅₀, nM) 1 1.06 2 4.35 3 3.08 49.35 5 2.36 6 1.86 7 1.29 8 1.69 9 1.26 10 3.55 11 3.66 12 3.76 13 1.7414 1.53 15 6.40 16 67.00 17 3.78 18 3.50 19 2.42 20 8.54 21 7.34 2223.56 24 6.31 25 2.04 27 4.29 32 0.57 33 0.67 34 0.48 35 0.49 36 0.38 370.36 38 0.68 39 0.53 40 0.47 41 8.68 42 1.05 43 0.60 44 1.21 45 1.03 461.64 47 0.69 48 1.03 49 2.02 50 1.88 51 1.19 52 0.56 53 1.48 54 1.47 550.69 56 0.74 57 1.66 58 1.22 59 4.81 60 4.18 61 1.00 62 0.84 63 4.04 651.08 66 0.57 67 4.54 68 3.37 70 1.48 71 0.50 72 7.19 73 2.18 74 1.57 752.14 76 6.66 77 2.18 78 0.95 80 3133 81 22.13 82 1.32 83 0.39 84 65.0185 1.49 86 0.56 87 1.11 88 1.10 89 0.79 90 4.91 91 9.05 92 0.72 93 0.7194 2.21 95 0.69 96 0.23 97 0.36 98 0.29 99 48.66 100 0.76 101 0.92 1020.72 103 1.39 104 0.85 105 1.06 106 1.59 107 1.09 108 1.43 109 0.45 1100.41 111 0.23 112 0.36 113 0.35 114 0.31

TABLE 2 Example No. PRP Assay (Gamma Thrombin IC₅₀, nM) 2 4459.00 134.91 18 68.19 23 628.80 26 970.30 28 24.55 29 93.41 30 124.60 31 49.9032 2773.00 40 2.86 48 65.88 53 3.63 59 2670.00 60 81.35 63 2426.00 64489.70 68 2230.00 69 13.08 71 3.61 81 4996.00 93 105.10 97 2.97 98 1.67100 1.80 110 87.64

Example G Cynomolgus Monkey Electrolytic Injury-Induced Carotid ArteryThrombosis Model

Healthy cynomolgus monkeys are used in the study. These monkeys areretired from other pharmacokinetic and pharmacodynamic studies and haveat least a 4-week washout period.

On the day of the study, compounds or vehicles are administered orallyat 1 to 2 hours before the experiment. Monkeys are then sedated byintramuscular administration of 0.2 mg/kg atropine, 5 mg/kg TELAZOL®(tiletamine/zolazepam) and 0.1 mg/kg hydromorphone to facilitateplacement of an endotracheal tube. An intravenous catheter is placed inthe left cephalic vein for fluid administration to prevent dehydration.Animals are then administered with an inhalant anesthetic, isoflurane(1-5% to effect) and oxygen, ventilated, and placed on athermostatically controlled heating pad to maintain the body temperatureat 37° C. General anesthesia is maintained at a surgical plane usinginhaled isoflurane and oxygen. The left brachial artery is cannulated torecord blood pressure and heart rate. Blood pressure and heart rate aremonitored to maintain normal vital signs.

The carotid arterial thrombosis model in monkeys is based on a rabbitarterial thrombosis model, as described by Wong et al. (Wong, P. C. etal., “Nonpeptide factor Xa inhibitors: II. Antithrombotic evaluation ina rabbit model of electrically induced carotid artery thrombosis”, J.Pharmacol. Exp. Ther., 295:212-218 (2002).) Thrombosis is induced byelectrical stimulation of the carotid artery for 5 min at 10 mA using anexternal stainless-steel bipolar electrode. Carotid blood flow ismeasured with an appropriately sized TRANSONIC® flow probe and aTRANSONIC® perivascular flowmeter (TS420 Model, Transonic Systems Inc.,Ithaca, N.Y.). It is continuously recorded over a 90-min period tomonitor thrombosis-induced occlusion. Integrated carotid blood flow ismeasured by the area under the flow-time curve. It is expressed aspercent of total control carotid blood flow, which would result ifcontrol blood flow has been maintained continuously for 90 min. Inaddition, thrombus from the injured artery is removed, blotted twice ona weighing paper to remove residual fluid, and weighed.

While it is apparent that the embodiments of the application hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present application.

What we claim is:
 1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: W is O or S; R¹ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; C₁-C₄ alkylthio, C₁-C₄ alkylNH—, (C₁-C₄ alkyl)₂N—, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R^(1a) is independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; C₁-C₄ alkylthio, C₁-C₄ alkylNH—, (C₁-C₄ alkyl)₂N—, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R⁸ and R⁹ are independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂ alkyl, halo-C₁-C₂ alkoxy, CN, and OH; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is selected from the group consisting of: H, halo, C₁-C₄ alkyl, alkoxy, and cyano; X¹ is selected from the group consisting of CH, N or CR¹⁰; X², X³ and X⁴ are independently selected from CR³ or N; R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano; R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl; or R⁴ and R⁵ can be taken together with the carbon to which they are attached to form a C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups; B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-membered heteroaryl, a 4-to 10-membered heterocyclyl containing carbon atoms and 1 to 4 additional heteroatoms selected from N, O, and S, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R^(b) groups; R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkyl sulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₆-C₁₀ aryl, 5-6-membered heteroaryl, 4- to 10-membered heterocyclyloxy and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to 10-membered heterocyclyloxy and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₁-C₄ alkyleneoxy-C₁-C₄-alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, di-C₁-C₄-alkylaminophenyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, phenylcarbonyl; C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, amino-C₁-C₄-alkylcarbonyl, 4- to 10-membered-heterocyclyl-carbonyl, and alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to 10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and p, at each occurrence, is selected from 0, 1 and
 2. 2. The compound as defined in claim 1, wherein the compound is a compound of formula IAA:


3. The compound of claim 2 wherein: W is O; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—;

is phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups;

is attached at the meta position of

and is selected from the group consisting of C₆-C₁₀ aryl ring, a 5- to 10-membered heteroaryl ring, a 4- to 10-membered heterocyclyl ring or a C₃-C₆-membered cycloalkyl ring, wherein each

rings is substituted with 0 to 3 R^(b) groups; R¹ is selected from the group consisting of: halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, and C₁-C₄ alkylthio; R^(1a) is selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, and C₁-C₄ alkylthio; R⁸ and R⁹ are independently selected from the group consisting of: H, C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, CF₃, CF₃O, CHF₂, and OH; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, and cyano; X¹ is selected from the group consisting of CH, N or Ce; X², X³ and X⁴ are independently selected from CR³ or N; R³ is selected from the group consisting of H, C₁-C₄ alkoxy, halo, CF₃O, CHF₂O, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens; R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl, or R⁴ and R⁵ can be taken together with the carbon to which they are attached to form a C₃-C₆ cycloalkyl ring; R^(a) is, at each occurrence, independently selected from the group consisting of: H, halo, OCF₃, NR⁶R⁷, OCHF₂, halo-C₁-C₂-alkyl substituted with 1 to 5 fluorines, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, OH, CN, NO₂, COOH, C₁-C₄ alkoxycarbonyl, C(═O)NR⁶R⁷, C₁-C₄ alkylsulfonyl, and S(═O)₂NR⁶R⁷; R^(b) is, at each occurrence, independently selected from the group consisting of: H, halo, OCF₃, NR⁶R⁷, OCHF₂, halo-C₁-C₂-alkyl substituted with 1 to 5 fluorines, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, OH, CN, NO₂, COOH, C₁-C₄ alkoxycarbonyl, C(═O)NR⁶R⁷, C₁-C₄ alkylsulfonyl, and S(═O)₂NR⁶R⁷; or R⁶ and R⁷ are, independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, and —(CH₂)_(n) ¹ phenyl, alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 6-membered heterocyclic ring containing carbon atoms and 1 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₄ alkyl and —(CH₂)phenyl; n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 and 5; and p, at each occurrence, is selected from 0, 1 and
 2. 4. The compound of claim 3, wherein the compound is a compound of formula IA or IB:


5. The compound of claim 4 wherein: W is O or S; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, and halo-C₁-C₂ alkoxy; R^(1a) is independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, and halo-C₁-C₂ alkoxy; R⁸ and R⁹ are independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂ alkyl, halo-C₁-C₂ alkoxy, and OH; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is selected from the group consisting of: H, halo, C₁-C₄ alkyl, and C₁-C₄ alkoxy; X¹ is selected from the group consisting of CH, N or CR¹⁰; X², X³ and X⁴ are independently selected from CR³ or N; R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, which contains 1 to 5 halogens, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano; R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵ can be taken together with the carbon to which they are attached to form a C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups; B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-membered heteroaryl, a 4-to 10-membered heterocyclyl containing carbon atoms and 1 to 4 additional heteroatoms selected from N, O, and S, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R^(b) groups; R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁—O₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₁-C₄ alkyleneoxy-C₁-C₄-alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, di-C₁-C₄-alkylaminophenyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, phenylcarbonyl; and alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 6-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), and —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and p, at each occurrence, is selected from 0, 1 and
 2. 6. The compound of claim 5 wherein: W is O or S; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; C₁-C₄ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R^(1a) is independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂ alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; C₁-C₄ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R⁸ and R⁹ are independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂ alkyl, and halo-C₁-C₂ alkoxy; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is selected from the group consisting of: H, halo, C₁-C₃ alkyl, and C₁-C₂ alkoxy; X¹ is selected from the group consisting of CH, N or C¹⁰; X², X³ and X⁴ are independently selected from CR³ or N; R³ is selected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, and —(CH₂)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano; R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵ can be taken together with the carbon to which they are attached to form a C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups; B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl containing carbon atoms and 1 to 4 additional heteroatoms selected from N, O, and S, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R^(b) groups; R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₁-C₄ alkyleneoxy-C₁-C₄-alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, phenylcarbonyl; C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, amino-C₁-C₄-alkylcarbonyl, 4- to 10-membered-heterocyclyl-carbonyl, and alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to 10-membered heteroarylcarbonylamino) and —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; n¹, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and p, at each occurrence, is selected from 0, 1 and
 2. 7. The compound of claim 6 wherein: W is O or S; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R^(1a) is independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R⁸ and R⁹ are independently selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₂ alkyl, and halo-C₁-C₂ alkoxy; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is selected from the group consisting of: H, fluoro, chloro, and CH₃; X¹ is selected from the group consisting of CH, N or CR¹⁰; X², X³ and X⁴ are independently selected from CR³ or N; R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylthio, halo, OH, CN, OCF₃, and halo-C₁-C₃-alkyl, which contains 1 to 5 halogens; R⁴ and R⁵ are independently selected from H, C₁-C₃ alkyl, halo-C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl, and C₁-C₃ alkoxy-C₁-C₃ alkyl, or R⁴ and R⁵ can be taken together with the carbon to which they are attached to form a C₃-C₇ cycloalkyl ring;

is phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R^(a) groups; B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl containing carbon atoms and 1 to 4 additional heteroatoms selected from N, O, and S, and a C₃-C₈ cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R^(b) groups; R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁—O₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₁-C₄ alkyleneoxy-C₁-C₄-alkylene, C₂-C₄ alkenyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, phenylcarbonyl; C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, amino-C₁-C₄-alkylcarbonyl, 4- to 10-membered-heterocyclyl-carbonyl, and alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino) and —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; n¹, at each occurrence, is selected from 0, 1, 2, 3 or 4; and p, at each occurrence, is selected from 0, 1 and
 2. 8. The compound of claim 7 wherein: W is O; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: halo, C₁-C₂ alkyl, cyclopropyl, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, and halo-C₃-C₄ cycloalkyl; R^(1a) is independently selected from the group consisting of: H, halo, C₁-C₂ alkyl, cyclopropyl, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl, and halo-C₃-C₄ cycloalkyl; R⁸ and R⁹ are independently selected from the group consisting of: H, fluoro, chloro, C₁-C₃ alkyl, C₁-C₂ alkoxy, and halo-C₁-C₂ alkyl; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is H; X¹ is selected from the group consisting of CH or N; X², X³ and X⁴ are independently selected from CR³; R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₁-C₃ alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens; R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, halo-C₁-C₃ alkyl, hydroxy-C₁-C₃ alkyl and C₁-C₃ alkoxy-C₁-C₃ alkyl;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; B is selected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl containing carbon atoms and 1 to 2 additional heteroatoms selected from N, O, and S, and a C₃-C₆ cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R^(b) groups; R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₂-C₄ alkenyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, phenylcarbonyl; C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl, and di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino and —(CH₂)_(n) ¹phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, n¹, at each occurrence, is selected from 0, 1, 2 or 3; and p, at each occurrence, is selected from 0, 1 and
 2. 9. The compound of claim 8 wherein: W is O; R⁰ is R¹ or R^(1a); Y is S or —CR⁸═CR⁹—; R¹ is independently selected from the group consisting of: C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ alkylthio, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; R^(1a) is independently selected from the group consisting of: H, fluoro, chloro, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ alkylthio, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, where halo is F or Cl; R⁸ and R⁹ are independently selected from the group consisting of: H, fluoro, chloro, CH₃, OCH₃, CF₃, and CHF₂; provided that at least one of R^(1a), R⁸ and R⁹ is other than H; R² is H; X¹ is selected from the group consisting of CH or N; X² and X⁴ are CH; X³ is CR³; R³ is selected from the group consisting of H, C₁-C₃ alkyl, C₁-C₃ alkoxy, fluoro, chloro, OCF₃, and halo-C₁-C₂-alkyl, which contains 1 to 5 halogens; R⁴ and R⁵ are independently selected from H and C₁-C₆ alkyl;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl;

is selected from the group consisting of phenyl, naphthyl pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁—O₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cyclo alkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₂-C₄ alkenyl, —(CR¹⁴R¹⁴)_(n) ¹-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n) ¹—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n) ¹-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbonyl, and phenylcarbonyl; alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H, and C₁-C₃ alkyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H, C₁-C₃ alkyl, and halo-C₁-C₂-alkyl; n¹, at each occurrence, is selected from 0, 1, 2 or 3; and p, at each occurrence, is selected from 0, 1 and
 2. 10. The compound of claim 9 wherein: W is O; R⁰ is R¹ or R^(1a); Y is S or —CH═CH—; R¹ is independently selected from the group consisting of: CH₃, OCH₃, SCH₃, CHFCH₃, and CF₂CH₃; R^(1a) is independently selected from the group consisting of: chloro, CH₃, and OCH₃, R² is H; X¹ is CH; X² and X⁴ are CH; X³ is CR³; R³ is selected from the group consisting of OCH₃, fluoro, and chloro; R⁴ and R⁵ are independently selected from H and CH₃;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl;

is selected from the group consisting of phenyl, naphthyl pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl,

R^(a), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R^(b), at each occurrence, is independently selected from the group consisting of H, halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, NR⁶R⁷, COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR⁶R⁷, C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR⁶R⁷, N(R¹³)(C═O)NR⁶R⁷, N(R¹³)(C═O)OR¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR⁶R⁷, O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, 5-6-membered heteroaryl, and C₁-C₅ alkyl substituted by 0 to 7 groups independently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl, (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino, C₃-C₆-cycloalkyl, phenyl, and C₁-C₄ alkylthio; R⁶ and R⁷ are independently, at each occurrence, selected from the group consisting of: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, di-C₁-C₄-alkylamino-C₁-C₄-alkyl, di-C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, and C₁-C₄-alkoxycarbonyl; alternatively, R⁶ and R⁷, when attached to the same nitrogen, combine to form a 4- to 7-membered heterocyclic ring containing carbon atoms substituted by 0 to 2 groups independently selected from the group consisting of halo, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, OH, oxo, hydroxy-C₁-C₂-alkyl, C₁-C₃ alkyl and C₁-C₃ alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³, 0 and S(O)_(p); R¹³ is independently, at each occurrence, selected from the group consisting of H and C₁-C₃ alkyl; R¹⁴ is independently, at each occurrence, selected from the group consisting of H and C₁-C₃ alkyl n¹, at each occurrence, is selected from 0, 1, 2 or 3; and p, at each occurrence, is selected from 0, 1 and
 2. 11. The compound of claim 10 wherein: X₁ is CH or N; R¹ is C₁-C₃ alkoxy or halo-C₁-C₂-alkyl which contains 1 to 5 halogens; R² is H; R³ is H, alkoxy or halogen;

is selected from the group consisting of phenyl, pyridyl and pyrimidinyl, all of which are substituted with 0 to 2 R^(a) groups;

is selected from the group consisting of: a) phenyl; b) phenyl substituted with 1 to 2 R^(b) substituents selected from halo, OH. halo-C₁-C₂-alkyl, which contains 1 to 5 halogens, CN, NO₂,

N(alkyl)₂, CF₃, C₁-C₄ alkyl, and C₁-C₄ alkoxy; c) phenyl fused to a heterocyclo group; d) monocyclic heteroaryl containing 5 or 6 ring members which contain: 1 oxygen atom, 2 nitrogen atoms, 2 sulfur atoms, 1 nitrogen atom, 1 sulfur atom, 1 oxygen atom, or combinations thereof, which monocyclic heteroaryl is substituted with 0 to 2 R^(b) substituents selected from halo, CN, NO₂, OH, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy,

N(alkyl)₂, C₁-C₄ alkoxy-C₁-C₄ alkoxy, COOH, alkoxycarbonyl, heterocyclyl, or heterocyclylcarbonyl; and e) bicyclic heteroaryl containing 8 or 9 ring members and which contains a sulfur atom, nitrogen atoms or combinations thereof in the ring.
 12. The compound as of claim 1, wherein the compound is selected from one of the examples.
 13. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a compound of claim 1, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, alone or in combination with another therapeutic agent.
 14. A method for the treatment of a thromboembolic disorder or the primary or secondary prophylaxis of a thromboembolic disorder, which comprises the steps of administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
 15. A method of inhibiting or preventing platelet aggregation, which comprises the step of administering to a subject in need thereof a therapeutically effective amount of a PAR4 antagonist, of claim
 1. 